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REVIEW |
Dipartimento di Genetica, Biologia e Biochimica, Molecular Biotechnology Center, University of Torino, Via Nizza 52, Torino 10126, Italy
(Requests for offprints should be addressed to E Hirsch; Email: emilio.hirsch{at}unito.it)
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Abstract |
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 Top Abstract Signal transduction: a matter...PtdInsPs and PI3KPI3K as a common...PI3K signaling in insulin...How can different hormones...References |
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Signal transduction: a matter of amplifiers |
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TopAbstractSignal transduction: a matter...PtdInsPs and PI3KPI3K as a common...PI3K signaling in insulin...How can different hormones...References |
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PtdInsPs and PI3K |
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TopAbstractSignal transduction: a matter...PtdInsPs and PI3KPI3K as a common...PI3K signaling in insulin...How can different hormones...References |
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Whereas inositol and its phosphorylated derivatives are found in bacteria, it is only in eukaryotes that PtdIns and its phosphorylated products (phosphoinositides) appear as lipid components of cell membranes involved in signaling (Michell 2007). Phosphoinositides are present in yeast and they are likely evolved as a means to mark membranes and regulate organelle identity as well as vesicular trafficking (Di Paolo & De Camilli 2006). In contrast to other types of signaling molecules, PtdIns phosphates label the membrane–cytosol interface without diffusion from one isolated membrane to another, thus stably marking, for example, vesicles and organelles. Enzymes that produce or degrade phosphoinositides probably evolved as a spatially restricted machinery that specifically scores membranes, promoting segregation of different compartments and providing a code to identify the fate of vesicles in their intracellular traffic. Similarly, protein binding to phosphoinositides could have appeared to ensure detection of such code as well as achievement of the targeted membrane fusion necessary for vectorial vesicular traffic. A further wave of diversification, dated at least one billion years ago, probably led to the appearance of the signaling properties of phosphoinositides and their derivatives. It is likely that the first signaling mechanisms involving PtdIns to appear in eukaryotes was the metabolism of PtdIns(4,5)P2 (also known as PIP2). PIP2 is diffusely present in the plasma membrane in resting conditions but is hydrolyzed to diacylglycerol (DAG) and inositol(1,4,5)trisphosphate (also known as IP3) upon receptor activation. IP3 and DAG are then able to trigger signal cascades involving Ca2+ release from intracellular stores and protein kinase C (PKC) activation respectively (Berridge 2005).
Though the effects of constitutive PtdIns production (Di Paolo & De Camilli 2006) and PIP2 metabolism (Berridge 2005) are of well-established importance, this review will focus on the mechanisms of production and on the biological effects of PtdIns phosphorylated at the D3 hydroxyl of the inositol ring, where the D prefix determines the direction of the phosphate away from the viewer (i.e. when the rings drawn in Fig. 1
are viewed from above; Hinchliffe & Irvine 1997). Cells contain at least four species of PtdIns phosphorylated in the D3 position (Fig. 1): PtdIns3P, PtdIns(3,4)P2, PtdIns(3,5)P2, and PtdIns(3,4,5)P3 (also known as phosphatidyl inositol phosphate3 (PIP3)). While PtdIns3P can be found in lower eukaryotes like yeasts, PtdIns(3,4)P2 and PIP3 appear in the phylogenetic tree with ameboid organisms and are detectable in nearly all higher eukaryotic cells, with the exclusion of plants that so far have never been described to produce PIP3 (Vanhaesebroeck et al. 2001). In a resting cell, only PtdIns3P can be detected and, though the other D3-phosphorylated molecular forms are virtually absent, they appear as pulses with different kinetics after receptor stimulation.
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Turnover of phosphoinositides is assured by the concerted action of kinases and phosphatases, and phosphoinositide 3-kinases (PI3K) are responsible for the phosphorylation of the D3 position of PtdIns. The number of PI3K present in different organisms varies throughout the phylogenetic tree: whereas yeast possesses only one PI3K gene, mammalian cells carry at least eight different genes with significant degrees of homology (Engelman et al. 2006). Some of these mammalian proteins are not only lipid kinases but also protein kinases, suggesting a possible origin from a class of distantly related protein kinases including mTOR (mammalian target of rapamycin) and DNA-PK. In the recent past, our notions on how PI3K works has tremendously increased and presently these kinases can be divided into three classes depending on their substrate specificity and ways of activation (Hawkins et al. 2006).
It is now clear, for example, that class I PI3K phosphorylate in vivo PIP2 to produce PIP3 and that class III enzymes produce PtdIns3P from PtdIns (Engelman et al. 2006). Nonetheless, the activity of class II PI3K is still debated and probably they are involved in the production of both PIP3 and PtdIns3P (Engelman et al. 2006). So far, though mounting evidences indicate that classes II and III PI3K might be involved in vesicular trafficking (Maffucci et al. 2003, Lindmo & Stenmark 2006), class I PI3K represent the best characterized type. Class I PI3K are usually heterodimers consisting of a catalytic subunit and an adaptor/regulator subunit. All class I catalytic subunits share substantial homology, show a molecular mass of ~110 kDa, and are collectively referred to as p110 subunits. Mammals possess four class I PI3K p110 genes named Pik3ca, Pik3cb, Pik3cg, and Pik3cd that are, however, usually termed PI3K
, ß, 
, and 
. While Pik3ca and Pik3cb are ubiquitously expressed, Pik3cg and Pik3cd are preferentially found in leukocytes, with the exception of Pik3cg being recently detected in the cardiovascular system (Hirsch et al. 2006). Proteins encoded by these genes share four regions of highest homology that comprises, from the N-terminal end, the domain for binding to the small GTPase Ras, the lipid-binding C2 domain, the PIK domain (a helical motif common to all PI3K), and the catalytic domain. Of these four enzymes, only the structure of PI3K has been resolved (Walker et al. 1999). The catalytic pocket of PI3K shows a two-lobe organization, where the first is involved in ATP binding (through a fundamental lysine residue found in all PI3K) and the second is more involved in substrate specificity (Walker et al. 1999). This catalytic cleft is able to specifically accommodate small molecule inhibitors that like wortmannin and LY294002 effectively block enzymatic activity of all PI3K (Walker et al. 2000). Nonetheless, the presence in the pocket of residues specific to the PI3K isoform allows the generation of selective inhibitors able to act more specifically on PI3K (Camps et al. 2005). While binding of PI3K to Ras has been described at atomic resolution (Pacold et al. 2000), an in-depth description of the structural details leading to the interaction of p110s with their adaptor/regulator subunit is still missing.
Two class I PI3K types
The presence of different families of adaptor/regulator subunits defines two subgroups in the family of class I PI3K. PI3K, ß, and enzymes bind to adaptor/regulators of the so-called p85 family and embody the IA subgroup (Fig. 2). Of these p85 adaptor/regulators, three genes named Pik3r1, Pik3r2, and Pik3r3 are found in mammals. Pik3r1 can be expressed in three splice variants that encode p85, p55, and p50 respectively; on the other hand, Pik3r2 and Pik3r3 are known to present only one transcript and encode p85ß and p55 respectively. While p85 and p85ß are ubiquitously expressed (Gout et al. 1992), p50 and p55 are present in fat, muscle, liver, and brain (Antonetti et al. 1996, Inukai et al. 1996), and p55 is mainly expressed in the brain (Pons et al. 1995). All members of the p85 family contain a p110-binding region tethering them to a specific domain located at the N-terminal end of class IA p110s. In p85 proteins, the p110-binding region is sandwiched between two SH2 domains and these two regions bind to phosphorylated tyrosine residues in the YXXM motif of tyrosine-phosphorylated receptors or receptor-associated adaptor signaling molecules. This property defines a way of activation peculiar to class IA PI3K that generally act downstream tyrosine kinase receptors. In the currently accepted model of class IA activation, p110 subunits are constitutively bound to p85 and kept inactive in the cytosol. Upon receptor activation, p85 is recruited to tyrosine-phosphorylated motifs and this event not only liberates the p85-mediated constraint on PI3K catalytic activity (Fu et al. 2003) but also localizes the enzyme next to the plasma membrane in the proximity of its lipid substrate (Yu et al. 1998). In addition to controlling activity and localization of PI3K, p85 family members possess specific activities: for example, p85 can control cell cycle in a p110-independent way (Garcia et al. 2006). In addition, p85 and ß contain an SH3 domain that ensures interaction with intracellular protoncogenes and oncogenes like Cbl or breakpoint cluster region (BCR)/Abl (Ren et al. 2005).
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, on the other hand, does not show an N-terminal p85-binding motif and interacts with the p101 (Stephens et al. 1997) and p84/87 adaptor/regulators (Suire et al. 2005, Voigt et al. 2005). PI3K is uniquely activated by G protein-coupled receptors (GPCR) and regulated by free Gß subunits of heterotrimeric G proteins usually of the Gi subtype (Hirsch et al. 2006). Interaction with Gß can be direct and sufficient to trigger enzymatic activity, but the presence of the non-catalytic adaptor/regulators facilitates this event by tethering PI3K to the plasma membrane (Brock et al. 2003). Interestingly, while PI3K is uniquely coupled to GPCR, the feature of being activated by Gß is probably shared with the class IA PI3Kß which can be promiscuously activated by both tyrosine kinase receptors and GPCR (Murga et al. 2000). On the other hand, like class IA PI3K, PI3K binds GTP-loaded Ras and this interaction can contribute to its activation, though to a limited extent (Suire et al. 2002). The binding of PI3K to Ras has, however, a crucial role in vivo in the triggering of reactive oxygen species (ROS) production (Suire et al. 2006). Interestingly, PI3K is not only acting like an enzyme but also possesses a scaffolding activity that controls the activation of the phosphodiesterase 3B, thus linking PI3K to the modulation of cAMP destruction and compartmentalization (Patrucco et al. 2004, Hirsch et al. 2006). PIP3 phosphatases
The product of class I PI3K activity is the substrate for a series of phosphatases that specifically remove phosphate groups from the inositol ring of PIP3. For example, hydrolysis of the phosphate in the D3 position is achieved by phosphatase and tensin homolog deleted on chromosome ten (PTEN) and is thought to terminate PI3K-mediated signaling (Cully et al. 2006). On the other hand, SH2-containing inositol 5'-phosphatase (SHIP) proteins are able to remove the phosphate in the D5 position, thus indicating that one mechanism of PtdIns(3,4)P2 appearance is due to PIP3 degradation (Kalesnikoff et al. 2003).
PI3K downstream effectors
Class I PI3K products exert their large number of biological functions because of their ability to function as docking sites for proteins that contain specific lipid-binding domains such as the pleckstrin homology (PH) domain. Interestingly, PH domain is more abundant in the human proteome, reaching the 11th position of the most common sequences (Lemmon 2007). PH domains are found with different sequence organization and specificities: some, like, for example, that found in Akt, specifically bind PIP3 but others, like the motif found in phospho lipase C (PLC) 1 (Lemmon et al. 1995), selectively interact with PIP2. Although not all PH domains containing proteins bind to phosphoinositides with sufficient strength for this to be of functional importance, the high number of proteins with such a domain highlights the complexity of signaling events downstream PI3K. A number of other protein domains are also able to bind to phosphoinositides 3-phosphate. For example, of note is the binding of the phox homology domain (PX; Xu et al. 2001) and domain present in Fab1, YOTB, Vac1 and EEA1 (FYVE) domains to PtdIns3P (Kutateladze 2006). For the sake of clarity, only the best characterized elements binding PIP3 will be further considered (Fig. 3).
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Although PKB/Akt is at the center stage of PI3K signaling, other well-characterized proteins can function as downstream targets of PIP3 production. It is worth mentioning, for example, that PI3K can trigger the activity of PH domain containing tyrosine kinases Tec and Btk (Lindvall & Islam 2002) or the phospholipase PLC (Maffucci & Falasca 2007). In addition, a PH domain is found in most activators of small GTPases of the Rho and Arf families (Hawkins et al. 2006), thus explaining the role of PI3K in cytoskeletal remodeling, and membrane trafficking respectively. On the other hand, emerging evidence indicates that GAP inhibitors of Rho GTPases can also be regulated by PIP3 binding and PI3K-mediated signaling (Di Paolo & De Camilli 2006). PI3K activity thus crucially controls the delicate balance between activating and inhibitory stimuli through, for example, the establishment of positive and negative feedback loops that help to transform shallow gradients of extracellular stimuli into robust cellular responses.
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PI3K as a common platform for hormonal signal transduction |
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TopAbstractSignal transduction: a matter...PtdInsPs and PI3KPI3K as a common...PI3K signaling in insulin...How can different hormones...References |
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PI3K and extranuclear estrogen receptor (ER) signaling
Estrogen actions are mediated by a mixture of both directly controlled gene expression (the so-called ‘genomic or classical’ action) and regulation of cell signaling/phosphorylation cascades, referred to as ‘non-genomic or extranuclear’ action. It is becoming increasingly evident that ER extranuclear signaling involves PI3K and might play central roles in controlling cell proliferation and survival (Fig. 4). Estrogen non-genomic effects on PI3K pathway might indeed be caused by direct interaction of the ER with PI3K (Migliaccio et al. 1996, Castoria et al. 2001), in a process that involves the p85 regulatory subunit binding to ER and a subsequent ER-dependent PKB/Akt activation (Simoncini et al. 2000, Castoria et al. 2001, Sun et al. 2001). An alternative ER-mediated mechanism for PI3K triggering can be found in a restricted number of breast cancer lines and depends on ER-induced ErbB2 activation that subsequently triggers PI3K recruitment/activation (Stoica et al. 2003). Through PI3K, ER also exerts its anti-apoptotic effects: in MCF7 breast cancer cells treated with 17ß-estradiol (E2), modulator of non-genomic action of ER (MNAR) functions as a scaffold for ER, cSrc, and p85 interactions, promoting PI3K activation and cell survival (Greger et al. 2007). Although ER controls PI3K activity, the opposite process has been described as well: in a number of epithelial cells, regulation of ER-dependent transcriptional activity can be a target of PI3K signaling, even in the absence of estrogen, through a mechanism that involves PKBß/Akt2-mediated phosphorylation of ER (Sun et al. 2001).
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-positive. Consistently, a recent study on 342 human breast tumor samples and tumor cell lines, at about equal frequency in tumor stages I–IV, reports the presence of Pik3ca mutations that are significantly associated with the expression of E and progesterone receptors (ER/PR; Saal et al. 2005). Taken together, these findings thus indicate a strong link between ER and PI3K pathways in human breast cancer.
This same signaling cascade is also found to play roles in ER-mediated control of cardiovascular functions (Fig. 4
). Estrogen, acting through ERs, plays a critical role in the protection of the cardiovascular system by pleiotropic effects, including vasodilatation, preservation of vascular integrity, and enhancement of cardiomyocyte survival by prevention of apoptosis. Indeed, estrogen-induced direct binding of ER to p85 increases PI3K activity and results in the activation of PKB/Akt, which in turn triggers eNOS-mediated NO production (Simoncini et al. 2000). The activation of NOS indeed reduces inflammatory reactions and protects from the effects of ischemia/reperfusion (Simoncini et al. 2000). Similarly, in an animal model of myocardial infarction, involving permanent coronary occlusion, E2-mediated activation of PI3K and PKB/Akt protects the heart by reducing both infarct size and myocyte apoptosis (Patten et al. 2004). Overall, the activation of the ER/PI3K/Akt/eNOS pathway thus explains, in cultured human endothelial cells as well as in vivo, in intact elastic and muscular arteries, the molecular mechanism underlying the long-known protective effects of estrogen on female cardiovascular system (Haynes et al. 2000, Guo et al. 2005).
On the other hand, this signaling pathway might modulate cardiovascular responses to hormones, like Ang II, that might play a role in heart failure and stroke. ER efficiently reduces Ang II- or endothelin 1 (ET1)-induced hypertrophy of individual cardiomyocytes, resulting in a smaller cell surface area and decreased cytoskeletal protein expression. This effect is mediated by the PI3K-dependent activation of MCIP1, a negative regulator of the NFAT transcription factor involved in cardiac hypertrophy (Pedram et al. 2005).
PI3K in Ang II signaling
PI3K might also play a role in the signaling pathways triggered by Ang II itself, the peptide hormone backbone of the rennin–angiotensin system that controls blood pressure homeostasis as well as myocardial cell growth. Ang II and its GPCRs (ATreceptors) play crucial roles by mediating smooth muscle growth, ROS production, and changes in vascular contractility. Indeed, the PI3K branch of Ang II-mediated signaling in vascular smooth muscle cells (VSMCs) is considered of increasing importance. For example, inhibition of PI3K activity with either LY294002 or wortmannin decreases AT1-receptor-stimulated activation of PKB/Akt (Takahashi et al. 1999), mTOR, and p70-S6 kinase as well as VSMC proliferation and gene expression (Saward & Zahradka 1997). Although Ang II regulates cell growth through the independent activation of PI3K and Erk1/2 pathways, it appears that both events are required for Ang II-induced proliferation of rat aortic smooth muscle cells (Dugourd et al. 2003).
In addition, Ang II controls vascular modulation of voltage-gated L-type Ca2+ channels by PI3K that thus appear as crucial regulators of Ca2+ entry and vascular excitation–contraction coupling. Ang II activates Ca2+ entry by stimulating L-type Ca2+ channels through Gß-sensitive PI3K in portal vein myocytes (Le Blanc et al. 2004). Although both PI3K and are expressed in vascular myocytes, Ang II-induced stimulation of vascular L-type Ca2+ channel and increase in Ca2+ depends only on the PI3K isoform (Macrez et al. 2001, Quignard et al. 2001). Similarly to VSMC, in cardiomyocytes, Ang II-evoked activation of PI3K, but not of PI3K, causes pathological cell growth (Naga Prasad et al. 2000). More recently, Vecchione et al. have demonstrated that PI3K plays a role in Ang II signaling in vivo (Fig. 5). Indeed, mice lacking PI3K are protected from hypertension induced by administration of Ang II. PI3K controls smooth muscle contraction via two distinct pathways: on the one hand, it triggers PKB/Akt activation and the subsequent entry of extracellular Ca2+ through L-type Ca2+ channels and, on the other hand, PIP3 produced by PI3K is necessary to trigger the small GTPase Rac possibly through the recruitment of PH domain containing GTP exchange factors (GEF). The activation of Rac, in turn, represents a critical step in the assembly at the plasma membrane and the subsequent activation of the NADPH oxidase complex triggering ROS production. These data indicate that PI3K is a key signaling molecule in the Ang II pathway and suggest that blocking PI3K function might be exploited to improve therapeutic intervention of hypertension (Vecchione et al. 2005).
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Leptin is another peptide hormone that modulates vascular tone as well as cell metabolism by stimulating PI3K. It binds the long form of leptin receptor (LRb) and triggers the tyrosine kinase JAK, eventually controlling STAT transcription factors and gene expression (Munzberg & Myers 2005). The way by which leptin also stimulates PI3K is not yet precisely defined, although different studies suggest JAK2-dependent and -independent mechanisms that trigger p85 binding to tyrosine-phosphorylated insulin receptor substrate (IRS, see below for description) adaptor proteins (Kellerer et al. 1997, Munzberg & Myers 2005, Mansour et al. 2006; Fig. 6). Although many effects of leptin are mediated through the central nervous system (for PI3K-mediated effects of leptin on the brain refer to review; Plum et al. 2005), this peptide can regulate metabolism through a direct action on tissues, such as pancreas and liver. In agreement with this finding, previous studies have shown that leptin activates PI3K in ß-cells and hepatocytes (Wang et al. 1997, Harvey et al. 2000, Szanto & Kahn 2000). Moreover, in primary rat hepatocytes, leptin induces PI3K-dependent activation of phosphodiesterase 3B, a cAMP-degrading enzyme, to suppress glucagon-induced cAMP elevation (Zhao et al. 2000). Leptin function in other tissues appears to similarly rely on PI3K signaling: for example, in VSMCs, leptin stimulates NOS activity and NO release, inhibiting the contractile response induced by Ang II, through mechanisms involving PKB/Akt and JAK2/STAT3 pathways (Rodriguez et al. 2007). On the other hand, it has recently become clear that leptin causes systemic effects on the regulation of immune function and some of these effects are PI3K mediated. Indeed, leptin causes a delayed apoptosis of mature neutrophils in vitro, through a signaling cascade involving PI3K (Bruno et al. 2005). Altogether, these indications suggest that leptin can induce PI3K signaling to influence different responses in distinct cell types.
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PI3K signaling in insulin-mediated metabolic control |
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TopAbstractSignal transduction: a matter...PtdInsPs and PI3KPI3K as a common...PI3K signaling in insulin...How can different hormones...References |
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). Activated insulin receptor (IR) triggers PI3K activity mainly by binding and phosphorylating adaptor proteins of the IRS family. IRS proteins are characterized by similar domains including a PH domain and a phosphotyrosine-binding domain, as well as by numerous tyrosine residues that can be phosphorylated by IR. Four different IRS proteins are expressed in mammals, though there are two additional IRS proteins detected in humans (IRS5/DOK4 and IRS6/DOK5) that are involved in insulin signaling but are not involved in PI3K activation (Cai et al. 2003). With a molecular weight ranging between 60 and 180 kDa, IRS proteins show differential tissue distribution as well as subcellular localization (Sun et al. 1997). While IRS-1 and IRS-2 are widely distributed (Araki et al. 1993, Sun et al. 1997), IRS-3 is limited to the brain, liver, adipocytes, and fibroblasts (Sciacchitano & Taylor 1997), and IRS4 is mainly expressed in embryonic tissues and adult muscle (Schreyer et al. 2003). Knockout mouse models indicate that IRS isoforms might play distinct roles: IRS-1-, IRS-2-, or IRS-4-deficient mice show defects on glucose homeostasis, with impaired glucose tolerance, increased serum triglycerides, and hepatic insulin resistance, but, in contrast, IRS-3 deficiency does not produce relevant effects on metabolism (Araki et al. 1994, Abe et al. 1998, Withers et al. 1998, Kubota et al. 2000). IRS activity downstream the IR is tightly regulated by positive and negative regulation. IRS is activated by tyrosine phosphorylation and negatively regulated by protein tyrosine phosphatases (Hayashi et al. 2004, Gonzalez-Rodriguez et al. 2007). Other inhibitory mechanisms include blockade of their binding to the IR (Ueki et al. 2002a), or serine phosphorylation mediated by a PI3K-mediated negative feedback that involves IRS phosphorylation by S6K (Um et al. 2004).
Upon phosphorylation by active IR, IRS serves as a docking site for SH2 domains of class IA p85 regulatory/adaptor subunits that consequently recruit p110 enzymes next to the activated receptor. PIP3 production in turn activates downstream effectors that control various metabolic processes such as glucose uptake, lipolysis inhibition, triglyceride formation, and glycogen synthesis. In these processes, the initiating event is the activation of PDK1 that, after PIP3 binding, activates atypical PKC (aPKC), PKB/Akt, and S6K (Vanhaesebroeck & Alessi 2000). Among these downstream effectors, PKB/Akt stimulates blood glucose disposal, promotes synthesis of glycogen, and inhibits gluconeogenesis. Three different isoforms of PKB/Akt, encoded by different genes, are found in mammals (PKB– or, alternatively, Akt1–3). All isoforms share a common structure including an N-terminal PH domain and a C-terminal catalytic domain. Recent data, obtained using knockout model mice, associate each PKB/Akt isoform with a specific function and indicate that not all are involved in insulin-mediated metabolic control. While PKB/Akt3 appears to be principally implicated in neuronal development (Tschopp et al. 2005), PKB/Akt1 is involved in growth and longevity (Chen et al. 2001, Cho et al. 2001a), but only PKBß/Akt2 is the main regulator in vivo of glucose homeostasis. Indeed, the absence of PKBß/Akt2 causes type 2 diabetes in both mice (Cho et al. 2001b) and humans (George et al. 2004).
Insulin, PI3K, and glucose metabolism
In adipocytes and muscle cells, PI3K-dependent activation of PKBß/Akt2 (and to a lesser extent of PKB/Akt1) controls insulin-mediated glucose uptake by stimulating GLUT4 translocation from an intracellular compartment to the plasma membrane (Katome et al. 2003). GLUT4 trafficking is controlled by PKB/Akt-mediated phosphorylation of the RabGAP (Rab GAP) AS160 (Akt substrate of 160 kDa) that when phosphorylated is inhibited by binding to 14-3-3 protein (Ramm et al. 2006). Other PI3K-dependent mediators of glucose uptake are atypical forms of PKC, including PKC
and PKC
isoforms. Overexpression of PKC and PKC produces an increase in GLUT4 translocation, which is, conversely, inhibited by a dominant-negative mutant of PKC (Bandyopadhyay et al. 1997).
Together with enzymes of class IA, PI3K of other classes might be involved in insulin-mediated glucose disposal. Recent experimental evidences suggest that insulin stimulation triggers the production of PtdIns3P, thus possibly involving either class II or III PI3K. For example, over-expression of myotubularins, the PtdIns3P phosphatases, reduces glucose uptake (Chaussade et al. 2003). PtdIns3P binds the PX and FYVE domains of proteins often involved in the control of vesicular trafficking. It is thus possible that PI3K other than class IA are involved in processes needed for plasma membrane fusion of cytoplasmic vesicles containing GLUT4 (Shepherd 2005). Interestingly, insulin-mediated PtdIns3P production appears insensitive to the action of wortmannin, thus excluding a role for class III enzymes but indicating a function of the wortmannin-insensitive class II PI3K-C2 isoenzymes (Maffucci et al. 2003). In line with this view, PI3K-C2 is activated in response to insulin-dependent (but PI3K-independent) activation of the small GTPase TC10, thus triggering PtdIns3P elevation necessary for full-scale GLUT4 plasma membrane translocation (Maffucci et al. 2003).
Another target of the class IA PI3K pathway is insulin-mediated inhibition of hepatic gluconeogenesis (Agati et al. 1998, Kotani et al. 1999). De novo synthesis of glucose is indispensable in a starved condition and, on the other hand, is dispensable when external resources are available. In this latter condition, insulin negatively regulates gluconeogenesis by suppressing the expression of key gluconeogenic enzymes through the PKB/Akt-mediated phosphorylation of the transcription factor FoxO1. After phosphorylation, FoxO1 is not able to translocate into the nucleus and consequently fails to activate transcription of various genes necessary for gluconeogenesis, such as phosphoenolpyruvate caboxykinase and glucose-6-phosphatase (Nakae et al. 2001).
Role of the regulatory subunit of PI3K
The crucial role of PI3K in insulin signaling suggests that its dysfunction may have deleterious effects on glucose homeostasis. Established lines of evidence indicate that PI3K signaling could be compromised by reducing expression of class IA PI3K enzymes and adaptors in type 2 diabetic ob/ob mice (Folli et al. 1993, Kerouz et al. 1997) as well as humans (Goodyear et al. 1995, Bjornholm et al. 1997, Rondinone et al. 1997).
Gene deletion studies of p85 regulatory subunits have challenged this view and reported unexpected paradoxical effects of loss of p85 proteins. Mice lacking p85, one of the three splicing variants encoded by the Pik3r1 gene, are viable but are hypoglycemic and show increased insulin sensitivity. However, this probably correlates with the up-regulation of the other Pik3r1 splicing variants, p50 and p55, in fat and muscle. This overexpression produces an elevation of PIP3 levels in adipocytes, which facilitates the GLUT4 translocation to the plasma membrane (Terauchi et al. 1999). On the contrary, deletion of the Pik3r1 gene, determining the ablation of all its products (p85, p55, and p50), results in perinatal lethality, extensive hepatocyte necrosis, enlarged skeletal muscle fibers, brown fat necrosis, and calcification of cardiac tissue. Loss of Pik3r1 causes a substantial decrease in expression and activity of class IA PI3K catalytic subunits. Nonetheless, Pik3r-deficient mice are hypoglycemic and more insulin sensitive than controls because of a more active glucose transport in insulin-responsive tissues like fat and muscle (Fruman et al. 2000). Furthermore, hepatic deletion of Pik3r1 produces similar paradoxical effects on PI3K activation/function. If, on the one hand, hepatic loss of Pik3r1 improves insulin sensitivity in liver, muscle, and fat, on the other hand, it leads to severe reduction in PI3K activation, with a 60% decrease in total hepatic PI3K activity (Taniguchi et al. 2006). Nonetheless, the activation of PKB/Akt downstream PI3K is enhanced as a consequence of reduced activity of the phosphatase PTEN, thus suggesting a role of p85 in PTEN regulation (Taniguchi et al. 2006). Indeed, PTEN is a potent negative regulator of the insulin signaling and loss of PTEN in adipose tissue results in an increased insulin sensitivity and GLUT4 recruitment (Kurlawalla-Martinez et al. 2005).
The paradoxical enhancement of insulin signaling is also detected in mice lacking either p50/p55 or p85ß. Although p50 and p55 are not required for survival, their loss produces a reduction in the insulin levels in the fasting state and an increase in glucose transport in isolated extensor digitorum longus (EDL) muscle and adipocytes (Chen et al. 2004). Similarly, mice lacking p85ß are viable and show hypoinsulinemia, hypoglycemia, and improved insulin sensitivity (Ueki et al. 2002b, 2003).
Taken together, these findings assign a positive and negative role to p85 regulatory subunits in the insulin signaling. In fact, p85 proteins are required for p110 stabilization but conversely free p85s exert negative effects on PI3K signaling. Therefore, a critical molecular balance between regulatory and catalytic subunits determines the optimal response of the PI3K pathway to insulin signaling (Ueki et al. 2002a). In physiological conditions, p85 is more abundant than the catalytic p110 subunit, producing a competition between p85 monomers and p85–p110 dimers. Monomers of p85 can thus inhibit PIP3 production either by binding to phosphorylated IRS proteins (Ueki et al. 2002a) or by altering subcellular localization of p110/p85 dimers (Inoue et al. 1998). Unbalancing p85 levels might thus compromise this regulatory mechanisms and lead to a paradoxical increase in PI3K activity. Finding of increased p85/55/50 protein expression, in mouse models of obesity as well as in type 2 diabetic patients, further confirms this view (Bandyopadhyay et al. 2005). Altogether, these findings suggest that p85 family members have a complex role in regulating PI3K-mediated insulin signaling that probably involves p110-independent activities yet to be fully understood.
Role of the catalytic subunit of PI3K
The use of no isoform-selective PI3K inhibitors has for long hindered the definition of the nature of the p110 catalytic subunits involved in insulin signaling. Nonetheless, recent reports using mutant mice as well as novel selective inhibitors suggest that different p110 subunits might play distinct roles. Although the lethal phenotype of mice lacking either p110 (p110–/–) or p110ß (p110ß–/–) hampered the study of their relative role in the insulin signaling, analysis of insulin-mediated responses in heterozygous animals suggests that both proteins might be involved. Heterozygous mice lacking either PI3K or ß show normal responses to insulin; however, p110+/–/p110ß+/– compound heterozygotes display decreased insulin sensitivity (Brachmann et al. 2005). Nonetheless, heterozygous mice expressing a catalytically inactive PI3K become insulin resistant with age. While young animals are normal, mice older than 6 months display glucose intolerance, hyperlipidemia, adiposity, as well as hyperglycemia and deregulate hepatic gluconeogenesis, thus assigning a fundamental role of PI3K in insulin-dependent signaling (Foukas et al. 2006). Biochemical analysis further shows that only PI3K is selectively recruited and activated by IRS proteins (Foukas et al. 2006). In agreement with this finding, the use of PI3K inhibitors with significant isoform selectivity shows that PI3K is the major PI3K effector downstream the IR and that, in contrast, PI3Kß maintains a marginal role (Knight et al. 2006). Nonetheless, inhibitor studies indicate that PI3Kß influences PI3K function providing a basal threshold of PIP3 production that potentiates PI3K activity, thus suggesting that PI3Kß function might be still necessary for achieving full scale signaling responses (Knight et al. 2006). Further studies with mice possibly expressing a catalytically inactive PI3Kß might help to address this issue.
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How can different hormones activate PI3K but exert different biological responses? |
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TopAbstractSignal transduction: a matter...PtdInsPs and PI3KPI3K as a common...PI3K signaling in insulin...How can different hormones...References |
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Acknowledgements |
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TopAbstractSignal transduction: a matter...PtdInsPs and PI3KPI3K as a common...PI3K signaling in insulin...How can different hormones...References |
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Agati JM, Yeagley D & Quinn PG 1998 Assessment of the roles of mitogen-activated protein kinase, phosphatidylinositol 3-kinase, protein kinase B, and protein kinase C in insulin inhibition of cAMP-induced phosphoenolpyruvate carboxykinase gene transcription. Journal of Biological Chemistry 273 18751–18759.
Antonetti DA, Algenstaedt P & Kahn CR 1996 Insulin receptor substrate 1 binds two novel splice variants of the regulatory subunit of phosphatidylinositol 3-kinase in muscle and brain. Molecular and Cellular Biology 16 2195–2203.[Abstract]
Araki E, Sun XJ, Haag BL III, Chuang LM, Zhang Y, Yang-Feng TL, White MF & Kahn CR 1993 Human skeletal muscle insulin receptor substrate-1. Characterization of the cDNA, gene, and chromosomal localization. Diabetes 42 1041–1054.[Abstract]
Araki E, Lipes MA, Patti ME, Bruning JC, Haag B III, Johnson RS & Kahn CR 1994 Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature 372 186–190.[CrossRef][Medline]
Bandyopadhyay G, Standaert ML, Zhao L, Yu B, Avignon A, Galloway L, Karnam P, Moscat J & Farese RV 1997 Activation of protein kinase C (alpha, beta, and zeta) by insulin in 3T3/L1 cells. Transfection studies suggest a role for PKC-zeta in glucose transport. Journal of Biological Chemistry 272 2551–2558.
Bandyopadhyay GK, Yu JG, Ofrecio J & Olefsky JM 2005 Increased p85/55/50 expression and decreased phosphotidylinositol 3-kinase activity in insulin-resistant human skeletal muscle. Diabetes 54 2351–2359.
Barthel A, Schmoll D & Unterman TG 2005 FoxO proteins in insulin action and metabolism. Trends in Endocrinology and Metabolism 16 183–189.[CrossRef][Web of Science][Medline]
Berridge MJ 2005 Unlocking the secrets of cell signaling. Annual Review of Physiology 67 1–21.[CrossRef][Web of Science][Medline]
Bjornholm M, Kawano Y, Lehtihet M & Zierath JR 1997 Insulin receptor substrate-1 phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle from NIDDM subjects after in vivo insulin stimulation. Diabetes 46 524–527.[Abstract]
Brachmann SM, Ueki K, Engelman JA, Kahn RC & Cantley LC 2005 Phosphoinositide 3-kinase catalytic subunit deletion and regulatory subunit deletion have opposite effects on insulin sensitivity in mice. Molecular and Cellular Biology 25 1596–1607.
Brock C, Schaefer M, Reusch HP, Czupalla C, Michalke M, Spicher K, Schultz G & Nurnberg B 2003 Roles of G beta gamma in membrane recruitment and activation of p110 gamma/p101 phosphoinositide 3-kinase gamma. Journal of Cell Biology 160 89–99.
Bruno A, Conus S, Schmid I & Simon HU 2005 Apoptotic pathways are inhibited by leptin receptor activation in neutrophils. Journal of Immunology 174 8090–8096.
Cai D, Dhe-Paganon S, Melendez PA, Lee J & Shoelson SE 2003 Two new substrates in insulin signaling, IRS5/DOK4 and IRS6/DOK5. Journal of Biological Chemistry 278 25323–25330.
Camps M, Ruckle T, Ji H, Ardissone V, Rintelen F, Shaw J, Ferrandi C, Chabert C, Gillieron C, Francon B et al. 2005 Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nature Medicine 11 936–943.[Web of Science][Medline]
Castoria G, Migliaccio A, Bilancio A, Di Domenico M, de Falco A, Lombardi M, Fiorentino R, Varricchio L, Barone MV & Auricchio F 2001 PI3-kinase in concert with Src promotes the S-phase entry of oestradiol-stimulated MCF-7 cells. EMBO Journal 20 6050–6059.[CrossRef][Web of Science][Medline]
Chaussade C, Pirola L, Bonnafous S, Blondeau F, Brenz-Verca S, Tronchere H, Portis F, Rusconi S, Payrastre B, Laporte J et al. 2003 Expression of myotubularin by an adenoviral vector demonstrates its function as a phosphatidylinositol 3-phosphate (PtdIns(3)P) phosphatase in muscle cell lines: involvement of PtdIns(3)P in insulin-stimulated glucose transport. Molecular Endocrinology 17 2448–2460.
Chen WS, Xu PZ, Gottlob K, Chen ML, Sokol K, Shiyanova T, Roninson I, Weng W, Suzuki R, Tobe K et al. 2001 Growth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene. Genes and Development 15 2203–2208.
Chen D, Mauvais-Jarvis F, Bluher M, Fisher SJ, Jozsi A, Goodyear LJ, Ueki K & Kahn CR 2004 p50alpha/p55alpha phosphoinositide 3-kinase knockout mice exhibit enhanced insulin sensitivity. Molecular and Cellular Biology 24 320–329.
Cho H, Thorvaldsen JL, Chu Q, Feng F & Birnbaum MJ 2001a Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. Journal of Biological Chemistry 276 2438349–38352.
Cho H, Mu J, Kim JK, Thorvaldsen JL, Chu Q, Crenshaw EB III, Kaestner KH, Bartolomei MS, Shulman GI & Birnbaum MJ 2001b Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 292 1728–1731.
Cross DA, Alessi DR, Cohen P, Andjelkovich M & Hemmings BA 1995 Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378 785–789.[CrossRef][Medline]
Cully M, You H, Levine AJ & Mak TW 2006 Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nature Reviews. Cancer 6 184–192.[CrossRef][Web of Science][Medline]
Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R & Zeiher AM 1999 Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 399 601–605.[CrossRef][Medline]
Di Paolo G & De Camilli P 2006 Phosphoinositides in cell regulation and membrane dynamics. Nature 443 651–657.[CrossRef][Medline]
Dugourd C, Gervais M, Corvol P & Monnot C 2003 Akt is a major downstream target of PI3-kinase involved in angiotensin II-induced proliferation. Hypertension 41 882–890.
Engelman JA, Luo J & Cantley LC 2006 The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nature Reviews. Genetics 7 606–619.[CrossRef][Web of Science][Medline]
Folli F, Saad MJ, Backer JM & Kahn CR 1993 Regulation of phosphatidylinositol 3-kinase activity in liver and muscle of animal models of insulin-resistant and insulin-deficient diabetes mellitus. Journal of Clinical Investigation 92 1787–1794.[Web of Science][Medline]
Foukas LC, Claret M, Pearce W, Okkenhaug K, Meek S, Peskett E, Sancho S, Smith AJ, Withers DJ & Vanhaesebroeck B 2006 Critical role for the p110alpha phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature 441 366–370.[CrossRef][Medline]
Fruman DA, Mauvais-Jarvis F, Pollard DA, Yballe CM, Brazil D, Bronson RT, Kahn CR & Cantley LC 2000 Hypoglycaemia, liver necrosis and perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85 alpha. Nature Genetics 26 379–382.[CrossRef][Web of Science][Medline]
Fu Z, Aronoff-Spencer E, Backer JM & Gerfen GJ 2003 The structure of the inter-SH2 domain of class IA phosphoinositide 3-kinase determined by site-directed spin labeling EPR and homology modeling. PNAS 100 3275–3280.
Garcia Z, Silio V, Marques M, Cortes I, Kumar A, Hernandez C, Checa AI, Serrano A & Carrera AC 2006 A PI3K activity-independent function of p85 regulatory subunit in control of mammalian cytokinesis. EMBO Journal 25 4740–4751.[CrossRef][Web of Science][Medline]
George S, Rochford JJ, Wolfrum C, Gray SL, Schinner S, Wilson JC, Soos MA, Murgatroyd PR, Williams RM, Acerini CL et al. 2004 A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science 304 1325–1328.
Gonzalez-Rodriguez A, Clampit JE, Escribano O, Benito M, Rondinone CM & Valverde AM 2007 Developmental switch from prolonged insulin action to increased insulin sensitivity in protein tyrosine phosphatase 1B-deficient hepatocytes. Endocrinology 148 594–608.
Goodyear LJ, Giorgino F, Sherman LA, Carey J, Smith RJ & Dohm GL 1995 Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. Journal of Clinical Investigation 95 2195–2204.[Web of Science][Medline]
Gout I, Dhand R, Panayotou G, Fry MJ, Hiles I, Otsu M & Waterfield MD 1992 Expression and characterization of the p85 subunit of the phosphatidylinositol 3-kinase complex and a related p85 beta protein by using the baculovirus expression system. Biochemical Journal 288 395–405.[Web of Science][Medline]
Greer EL & Brunet A 2005 FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 24 7410–7425.[CrossRef][Web of Science][Medline]
Greger JG, Fursov N, Cooch N, McLarney S, Freedman LP, Edwards DP & Cheskis BJ 2007 Phosphorylation of MNAR promotes estrogen activation of phosphatidylinositol 3-kinase. Molecular and Cellular Biology 27 1904–1913.
Guo X, Razandi M, Pedram A, Kassab G & Levin ER 2005 Estrogen induces vascular wall dilation: mediation through kinase signaling to nitric oxide and estrogen receptors alpha and beta. Journal of Biological Chemistry 280 19704–19710.
Harvey J, McKay NG, Walker KS, Van der Kaay J, Downes CP & Ashford ML 2000 Essential role of phosphoinositide 3-kinase in leptin-induced K(ATP) channel activation in the rat CRI-G1 insulinoma cell line. Journal of Biological Chemistry 275 4660–4669.
Hawkins PT, Anderson KE, Davidson K & Stephens LR 2006 Signalling through Class I PI3Ks in mammalian cells. Biochemical Society Transactions 34 647–662.[CrossRef][Web of Science][Medline]
Hayashi K, Shibata K, Morita T, Iwasaki K, Watanabe M & Sobue K 2004 Insulin receptor substrate-1/SHP-2 interaction, a phenotype-dependent switching machinery of insulin-like growth factor-I signaling in vascular smooth muscle cells. Journal of Biological Chemistry 279 40807–40818.
Haynes MP, Sinha D, Russell KS, Collinge M, Fulton D, Morales-Ruiz M, Sessa WC & Bender JR 2000 Membrane estrogen receptor engagement activates endothelial nitric oxide synthase via the PI3-kinase-Akt pathway in human endothelial cells. Circulation Research 87 677–682.
Hinchliffe K & Irvine R 1997 Inositol lipid pathways turn turtle. Nature 390 123–124.[CrossRef][Medline]
Hirsch E, Lembo G, Montrucchio G, Rommel C, Costa C & Barberis L 2006 Signaling through PI3Kgamma: a common platform for leukocyte, platelet and cardiovascular stress sensing. Thrombosis and Haemostasis 95 29–35.[Web of Science][Medline]
Inoue G, Cheatham B, Emkey R & Kahn CR 1998 Dynamics of insulin signaling in 3T3-L1 adipocytes. Differential compartmentalization and trafficking of insulin receptor substrate (IRS)-1 and IRS-2. Journal of Biological Chemistry 273 11548–11555.
Inukai K, Anai M, Van Breda E, Hosaka T, Katagiri H, Funaki M, Fukushima Y, Ogihara T, Yazaki Y, Kikuchi M et al. 1996 A novel 55-kDa regulatory subunit for phosphatidylinositol 3-kinase structurally similar to p55PIK is generated by alternative splicing of the p85alpha gene. Journal of Biological Chemistry 271 5317–5320.
Kalesnikoff J, Sly LM, Hughes MR, Buchse T, Rauh MJ, Cao LP, Lam V, Mui A, Huber M & Krystal G 2003 The role of SHIP in cytokine-induced signaling. Reviews of Physiology, Biochemistry and Pharmacology 149 87–103.[Web of Science][Medline]
Katome T, Obata T, Matsushima R, Masuyama N, Cantley LC, Gotoh Y, Kishi K, Shiota H & Ebina Y 2003 Use of RNA interference-mediated gene silencing and adenoviral overexpression to elucidate the roles of AKT/protein kinase B isoforms in insulin actions. Journal of Biological Chemistry 278 28312–28323.
Kellerer M, Koch M, Metzinger E, Mushack J, Capp E & Haring HU 1997 Leptin activates PI-3 kinase in C2C12 myotubes via janus kinase-2 (JAK-2) and insulin receptor substrate-2 (IRS-2) dependent pathways. Diabetologia 40 1358–1362.[CrossRef][Web of Science][Medline]
Kerouz NJ, Horsch D, Pons S & Kahn CR 1997 Differential regulation of insulin receptor substrates-1 and -2 (IRS-1 and IRS-2) and phosphatidylinositol 3-kinase isoforms in liver and muscle of the obese diabetic (ob/ob) mouse. Journal of Clinical Investigation 100 3164–3172.[Web of Science][Medline]
Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O, Loewith R, Stokoe D, Balla A, Toth B et al. 2006 A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell 125 733–747.[CrossRef][Web of Science][Medline]
Kotani K, Ogawa W, Hino Y, Kitamura T, Ueno H, Sano W, Sutherland C, Granner DK & Kasuga M 1999 Dominant negative forms of Akt (protein kinase B) and atypical protein kinase Clambda do not prevent insulin inhibition of phosphoenolpyruvate carboxykinase gene transcription. Journal of Biological Chemistry 274 21305–21312.
Kubota N, Tobe K, Terauchi Y, Eto K, Yamauchi T, Suzuki R, Tsubamoto Y, Komeda K, Nakano R, Miki H et al. 2000 Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory beta-cell hyperplasia. Diabetes 49 1880–1889.[Abstract]
Kurlawalla-Martinez C, Stiles B, Wang Y, Devaskar SU, Kahn BB & Wu H 2005 Insulin hypersensitivity and resistance to streptozotocin-induced diabetes in mice lacking PTEN in adipose tissue. Molecular and Cellular Biology 25 2498–2510.
Kutateladze TG 2006 Phosphatidylinositol 3-phosphate recognition and membrane docking by the FYVE domain. Biochimica et Biophysica Acta 1761 868–877.[Medline]
Le Blanc C, Mironneau C, Barbot C, Henaff M, Bondeva T, Wetzker R & Macrez N 2004 Regulation of vascular L-type Ca2+ channels by phosphatidylinositol 3,4,5-trisphosphate. Circulation Research 95 300–307.
Lemmon MA 2007 Pleckstrin homology (PH) domains and phosphoinositides. Biochemical Society Symposium 74 81–93.[CrossRef][Web of Science][Medline]
Lemmon MA, Ferguson KM, O’Brien R, Sigler PB & Schlessinger J 1995 Specific and high-affinity binding of inositol phosphates to an isolated pleckstrin homology domain. PNAS 92 10472–10476.
Liang J & Slingerland JM 2003 Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle 2 339–345.[Medline]
Lindmo K & Stenmark H 2006 Regulation of membrane traffic by phosphoinositide 3-kinases. Journal of Cell Science 119 605–614.
Lindvall J & Islam TC 2002 Interaction of Btk and Akt in B cell signaling. Biochemical and Biophysical Research Communications 293 1319–1326.[CrossRef][Web of Science][Medline]
Macrez N, Mironneau C, Carricaburu V, Quignard JF, Babich A, Czupalla C, Nurnberg B & Mironneau J 2001 Phosphoinositide 3-kinase isoforms selectively couple receptors to vascular L-type Ca(2+) channels. Circulation Research 89 692–699.
Maffucci T & Falasca M 2007 Phosphoinositide 3-kinase-dependent regulation of phospholipase Cgamma. Biochemical Society Transactions 35 229–230.[CrossRef][Web of Science][Medline]
Maffucci T, Brancaccio A, Piccolo E, Stein RC & Falasca M 2003 Insulin induces phosphatidylinositol-3-phosphate formation through TC10 activation. EMBO Journal 22 4178–4189.[CrossRef][Web of Science][Medline]
Mansour E, Pereira FG, Araujo EP, Amaral ME, Morari J, Ferraroni NR, Ferreira DS, Lorand-Metze I & Velloso LA 2006 Leptin inhibits apoptosis in thymus through a janus kinase-2-independent, insulin receptor substrate-1/phosphatidylinositol-3 kinase-dependent pathway. Endocrinology 147 5470–5479.
Michell RH 2007 Evolution of the diverse biological roles of inositols. Biochemical Society Symposium 74 223–246.[CrossRef][Web of Science][Medline]
Migliaccio A, Di Domenico M, Castoria G, de Falco A, Bontempo P, Nola E & Auricchio F 1996 Tyrosine kinase/p21ras/MAP-kinase pathway activation by estradiol-receptor complex in MCF-7 cells. EMBO Journal 15 1292–1300.[Web of Science][Medline]
Munzberg H & Myers MG Jr 2005 Molecular and anatomical determinants of central leptin resistance. Nature Neuroscience 8 566–570.[CrossRef][Web of Science][Medline]
Murga C, Fukuhara S & Gutkind JS 2000 A novel role for phosphatidylinositol 3-kinase beta in signaling from G protein-coupled receptors to Akt. Journal of Biological Chemistry 275 12069–12073.
Naga Prasad SV, Esposito G, Mao L, Koch WJ & Rockman HA 2000 Gbetagamma-dependent phosphoinositide 3-kinase activation in hearts with in vivo pressure overload hypertrophy. Journal of Biological Chemistry 275 4693–4698.
Nakae J, Kitamura T, Ogawa W, Kasuga M & Accili D 2001 Insulin regulation of gene expression through the forkhead transcription factor Foxo1 (Fkhr) requires kinases distinct from Akt. Biochemistry 40 11768–11776.[CrossRef][Medline]
Pacold ME, Suire S, Perisic O, Lara-Gonzalez S, Davis CT, Walker EH, Hawkins PT, Stephens L, Eccleston JF & Williams RL 2000 Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase gamma. Cell 103 931–943.[CrossRef][Web of Science][Medline]
Patrucco E, Notte A, Barberis L, Selvetella G, Maffei A, Brancaccio M, Marengo S, Russo G, Azzolino O, Rybalkin SD et al. 2004 PI3Kgamma modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects. Cell 118 375–387.[CrossRef][Web of Science][Medline]
Patten RD, Pourati I, Aronovitz MJ, Baur J, Celestin F, Chen X, Michael A, Haq S, Nuedling S, Grohe C et al. 2004 17beta-estradiol reduces cardiomyocyte apoptosis in vivo and in vitro via activation of phosphoinositide-3 kinase/Akt signaling. Circulation Research 95 692–699.
Pedram A, Razandi M, Aitkenhead M & Levin ER 2005 Estrogen inhibits cardiomyocyte hypertrophy in vitro. Antagonism of calcineurin-related hypertrophy through induction of MCIP1. Journal of Biological Chemistry 280 26339–26348.
Plum L, Schubert M & Bruning JC 2005 The role of insulin receptor signaling in the brain. Trends in Endocrinology and Metabolism 16 59–65.[CrossRef][Web of Science][Medline]
Pons S, Asano T, Glasheen E, Miralpeix M, Zhang Y, Fisher TL, Myers MG Jr, Sun XJ & White MF 1995 The structure and function of p55PIK reveal a new regulatory subunit for phosphatidylinositol 3-kinase. Molecular and Cellular Biology 15 4453–4465.[Abstract]
Quignard JF, Mironneau J, Carricaburu V, Fournier B, Babich A, Nurnberg B, Mironneau C & Macrez N 2001 Phosphoinositide 3-kinase gamma mediates angiotensin II-induced stimulation of L-type calcium channels in vascular myocytes. Journal of Biological Chemistry 276 32545–32551.
Ramm G, Larance M, Guilhaus M & James DE 2006 A role for 14-3-3 in insulin-stimulated GLUT4 translocation through its interaction with the RabGAP AS160. Journal of Biological Chemistry 281 29174–29180.
Ren SY, Bolton E, Mohi MG, Morrione A, Neel BG & Skorski T 2005 Phosphatidylinositol 3-kinase p85{alpha} subunit-dependent interaction with BCR/ABL-related fusion tyrosine kinases: molecular mechanisms and biological consequences. Molecular and Cellular Biology 25 8001–8008.
Rodriguez A, Fortuno A, Gomez-Ambrosi J, Zalba G, Diez J & Fruhbeck G 2007 The inhibitory effect of leptin on angiotensin II-induced vasoconstriction in vascular smooth muscle cells is mediated via a nitric oxide-dependent mechanism. Endocrinology 148 324–331.
Rondinone CM, Wang LM, Lonnroth P, Wesslau C, Pierce JH & Smith U 1997 Insulin receptor substrate (IRS) 1 is reduced and IRS-2 is the main docking protein for phosphatidylinositol 3-kinase in adipocytes from subjects with non-insulin-dependent diabetes mellitus. PNAS 94 4171–4175.
Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, Yu JS, Malmstrom PO, Mansukhani M, Enoksson J et al. 2005 PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutuallyexclusive with PTEN loss in human breast carcinoma. Cancer Research 65 2554–2559.
Sabatini DM 2006 mTOR and cancer: insights into a complex relationship. Nature Reviews. Cancer 6 729–734.[CrossRef][Web of Science][Medline]
Saward L & Zahradka P 1997 Angiotensin II activates phosphatidylinositol 3-kinase in vascular smooth muscle cells. Circulation Research 81 249–257.
Schmidt M, Fernandez de Mattos S, van der Horst A, Klompmaker R, Kops GJ, Lam EW, Burgering BM & Medema RH 2002 Cell cycle inhibition by FoxO forkhead transcription factors involves downregulation of cyclin D. Molecular and Cellular Biology 22 7842–7852.
Schreyer S, Ledwig D, Rakatzi I, Kloting I & Eckel J 2003 Insulin receptor substrate-4 is expressed in muscle tissue without acting as a substrate for the insulin receptor. Endocrinology 144 1211–1218.
Sciacchitano S & Taylor SI 1997 Cloning, tissue expression, and chromosomal localization of the mouse IRS-3 gene. Endocrinology 138 4931–4940.
Shepherd PR 2005 Mechanisms regulating phosphoinositide 3-kinase signalling in insulin-sensitive tissues. Acta Physiologica Scandinavica 183 3–12.[CrossRef][Web of Science][Medline]
Simoncini T, Hafezi-Moghadam A, Brazil DP, Ley K, Chin WW & Liao JK 2000 Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 407 538–541.[CrossRef][Medline]
Sonenberg N & Pause A 2006 Signal transduction. Protein synthesis and oncogenesis meet again. Science 314 428–429.
Stephens LR, Eguinoa A, Erdjument-Bromage H, Lui M, Cooke F, Coadwell J, Smrcka AS, Thelen M, Cadwallader K, Tempst P et al. 1997 The G beta gamma sensitivity of a PI3K is dependent upon a tightly associated adaptor, p101. Cell 89 105–114.[CrossRef][Web of Science][Medline]
Stoica GE, Franke TF, Wellstein A, Czubayko F, List HJ, Reiter R, Morgan E, Martin MB & Stoica A 2003 Estradiol rapidly activates Akt via the ErbB2 signaling pathway. Molecular Endocrinology 17 818–830.
Suire S, Hawkins P & Stephens L 2002 Activation of phosphoinositide 3-kinase gamma by Ras. Current Biology 12 1068–1075.[CrossRef][Web of Science][Medline]
Suire S, Coadwell J, Ferguson GJ, Davidson K, Hawkins P & Stephens L 2005 p84, a new Gbetagamma-activated regulatory subunit of the type IB phosphoinositide 3-kinase p110gamma. Current Biology 15 566–570.[CrossRef][Web of Science][Medline]
Suire S, Condliffe AM, Ferguson GJ, Ellson CD, Guillou H, Davidson K, Welch H, Coadwell J, Turner M, Chilvers ER et al. 2006 Gbetagammas and the Ras binding domain of p110gamma are both important regulators of PI(3)Kgamma signalling in neutrophils. Nature Cell Biology 8 1303–1309.[CrossRef][Web of Science][Medline]
Sun XJ, Pons S, Wang LM, Zhang Y, Yenush L, Burks D, Myers MG Jr, Glasheen E, Copeland NG, Jenkins NA et al. 1997 The IRS-2 gene on murine chromosome 8 encodes a unique signaling adapter for insulin and cytokine action. Molecular Endocrinology 11 251–262.
Sun M, Paciga JE, Feldman RI, Yuan Z, Coppola D, Lu YY, Shelley SA, Nicosia SV & Cheng JQ 2001 Phosphatidylinositol-3-OH Kinase (PI3K)/AKT2, activated in breast cancer, regulates and is induced by estrogen receptor alpha (ERalpha) via interaction between ERalpha and PI3K. Cancer Research 61 5985–5991.
Szanto I & Kahn CR 2000 Selective interaction between leptin and insulin signaling pathways in a hepatic cell line. PNAS 97 2355–2360.
Takahashi T, Taniguchi T, Konishi H, Kikkawa U, Ishikawa Y & Yokoyama M 1999 Activation of Akt/protein kinase B after stimulation with angiotensin II in vascular smooth muscle cells. American Journal of Physiology 276 H1927–H1934.[Web of Science][Medline]
Taniguchi CM, Tran TT, Kondo T, Luo J, Ueki K, Cantley LC & Kahn CR 2006 Phosphoinositide 3-kinase regulatory subunit p85alpha suppresses insulin action via positive regulation of PTEN. PNAS 103 12093–12097.
Terauchi Y, Tsuji Y, Satoh S, Minoura H, Murakami K, Okuno A, Inukai K, Asano T, Kaburagi Y, Ueki K et al. 1999 Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 alpha subunit of phosphoinositide 3-kinase. Nature Genetics 21 230–235.[CrossRef][Web of Science][Medline]
Thong FS, Dugani CB & Klip A 2005 Turning signals on and off: GLUT4 traffic in the insulin-signaling highway. Physiology 20 271–284.
Trotman LC, Alimonti A, Scaglioni PP, Koutcher JA, Cordon-Cardo C & Pandolfi PP 2006 Identification of a tumour suppressor network opposing nuclear Akt function. Nature 441 523–527.[CrossRef][Medline]
Tschopp O, Yang ZZ, Brodbeck D, Dummler BA, Hemmings-Mieszczak M, Watanabe T, Michaelis T, Frahm J & Hemmings BA 2005 Essential role of protein kinase B gamma (PKB gamma/Akt3) in postnatal brain development but not in glucose homeostasis. Development 132 2943–2954.
Ueki K, Fruman DA, Brachmann SM, Tseng YH, Cantley LC & Kahn CR 2002a Molecular balance between the regulatory and catalytic subunits of phosphoinositide 3-kinase regulates cell signaling and survival. Molecular and Cellular Biology 22 965–977.
Ueki K, Yballe CM, Brachmann SM, Vicent D, Watt JM, Kahn CR & Cantley LC 2002b Increased insulin sensitivity in mice lacking p85beta subunit of phosphoinositide 3-kinase. PNAS 99 419–424.
Ueki K, Fruman DA, Yballe CM, Fasshauer M, Klein J, Asano T, Cantley LC & Kahn CR 2003 Positive and negative roles of p85 alpha and p85 beta regulatory subunits of phosphoinositide 3-kinase in insulin signaling. Journal of Biological Chemistry 278 48453–48466.
Um SH, Frigerio F, Watanabe M, Picard F, Joaquin M, Sticker M, Fumagalli S, Allegrini PR, Kozma SC, Auwerx J et al. 2004 Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431 200–205.[CrossRef][Medline]
Vanhaesebroeck B & Alessi DR 2000 The PI3K-PDK1 connection: more than just a road to PKB. Biochemical Journal 346 561–576.[CrossRef][Web of Science][Medline]
Vanhaesebroeck B, Leevers SJ, Ahmadi K, Timms J, Katso R, Driscoll PC, Woscholski R, Parker PJ & Waterfield MD 2001 Synthesis and function of 3-phosphorylated inositol lipids. Annual Review of Biochemistry 70 535–602.[CrossRef][Web of Science][Medline]
Vecchione C, Patrucco E, Marino G, Barberis L, Poulet R, Aretini A, Maffei A, Gentile MT, Storto M, Azzolino O et al. 2005 Protection from angiotensin II-mediated vasculotoxic and hypertensive response in mice lacking PI3Kgamma. Journal of Experimental Medicine 201 1217–1228.
Viard P, Butcher AJ, Halet G, Davies A, Nurnberg B, Heblich F & Dolphin AC 2004 PI3K promotes voltage-dependent calcium channel trafficking to the plasma membrane. Nature Neuroscience 7 939–946.[CrossRef][Web of Science][Medline]
Voigt P, Brock C, Nurnberg B & Schaefer M 2005 Assigning functional domains within the p101 regulatory subunit of phosphoinositide 3-kinase gamma. Journal of Biological Chemistry 280 5121–5127.
Walker EH, Perisic O, Ried C, Stephens L & Williams RL 1999 Structural insights into phosphoinositide 3-kinase catalysis and signalling. Nature 402 313–320.[CrossRef][Medline]
Walker EH, Pacold ME, Perisic O, Stephens L, Hawkins PT, Wymann MP & Williams RL 2000 Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Molecular Cell 6 909–919.[CrossRef][Web of Science][Medline]
Wang Y, Kuropatwinski KK, White DW, Hawley TS, Hawley RG, Tartaglia LA & Baumann H 1997 Leptin receptor action in hepatic cells. Journal of Biological Chemistry 272 16216–16223.
Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM, Previs S, Zhang Y, Bernal D, Pons S, Shulman GI et al. 1998 Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391 900–904.[CrossRef][Medline]
Wullschleger S, Loewith R & Hall MN 2006 TOR signaling in growth and metabolism. Cell 124 471–484.[CrossRef][Web of Science][Medline]
Xu Y, Seet LF, Hanson B & Hong W 2001 The Phox homology (PX) domain, a new player in phosphoinositide signalling. Biochemical Journal 360 513–530.[CrossRef][Web of Science][Medline]
Yu J, Zhang Y, McIlroy J, Rordorf-Nikolic T, Orr GA & Backer JM 1998 Regulation of the p85/p110 phosphatidylinositol 3'-kinase: stabilization and inhibition of the p110alpha catalytic subunit by the p85 regulatory subunit. Molecular and Cellular Biology 18 1379–1387.
Zhao AZ, Shinohara MM, Huang D, Shimizu M, Eldar-Finkelman H, Krebs EG, Beavo JA & Bornfeldt KE 2000 Leptin induces insulin-like signaling that antagonizes cAMP elevation by glucagon in hepatocytes. Journal of Biological Chemistry 275 11348–11354.
Received in final form 12 April 2007
Accepted 16 April 2007
Made available online as an Accepted Preprint 17 April 2007
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 N. Thongon, L.-i. Nakkrasae, J. Thongbunchoo, N. Krishnamra, and N. Charoenphandhu Enhancement of calcium transport in Caco-2 monolayer through PKC{zeta}-dependent Cav1.3-mediated transcellular and rectifying paracellular pathways by prolactin Am J Physiol Cell Physiol, June 1, 2009; 296(6): C1373 - C1382. [Abstract] [Full Text] [PDF]
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 E. Ohashi, T. Kogai, H. Kagechika, and G. A. Brent Activation of the PI3 Kinase Pathway By Retinoic Acid Mediates Sodium/Iodide Symporter Induction and Iodide Transport in MCF-7 Breast Cancer Cells Cancer Res., April 15, 2009; 69(8): 3443 - 3450. [Abstract] [Full Text] [PDF]
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 M. Herrera, N. J. Hong, P. A. Ortiz, and J. L. Garvin Endothelin-1 Inhibits Thick Ascending Limb Transport via Akt-stimulated Nitric Oxide Production J. Biol. Chem., January 16, 2009; 284(3): 1454 - 1460. [Abstract] [Full Text] [PDF]
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 I. Esposito, M. C. Proto, P. Gazzerro, C. Laezza, C. Miele, A. T. Alberobello, V. D'Esposito, F. Beguinot, P. Formisano, and M. Bifulco The Cannabinoid CB1 Receptor Antagonist Rimonabant Stimulates 2-Deoxyglucose Uptake in Skeletal Muscle Cells by Regulating the Expression of Phosphatidylinositol-3-kinase Mol. Pharmacol., December 1, 2008; 74(6): 1678 - 1686. [Abstract] [Full Text] [PDF]
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 E. Ciraolo, M. Iezzi, R. Marone, S. Marengo, C. Curcio, C. Costa, O. Azzolino, C. Gonella, C. Rubinetto, H. Wu, et al. Phosphoinositide 3-Kinase p110{beta} Activity: Key Role in Metabolism and Mammary Gland Cancer but Not Development Sci. Signal., September 9, 2008; 1(36): ra3 - ra3. [Abstract] [Full Text] [PDF]
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 J. Wang, Z. A. Knight, D. Fiedler, O. Williams, K. M. Shokat, and D. Pearce Activity of the p110-{alpha} subunit of phosphatidylinositol-3-kinase is required for activation of epithelial sodium transport Am J Physiol Renal Physiol, September 1, 2008; 295(3): F843 - F850. [Abstract] [Full Text] [PDF]
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 A. Moeenrezakhanlou, L. Shephard, L. Lam, and N. E. Reiner Myeloid cell differentiation in response to calcitriol for expression CD11b and CD14 is regulated by myeloid zinc finger-1 protein downstream of phosphatidylinositol 3-kinase J. Leukoc. Biol., August 1, 2008; 84(2): 519 - 528. [Abstract] [Full Text] [PDF]
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 C. Fos, A. Salles, V. Lang, F. Carrette, S. Audebert, S. Pastor, M. Ghiotto, D. Olive, G. Bismuth, and J. A. Nunes ICOS Ligation Recruits the p50{alpha} PI3K Regulatory Subunit to the Immunological Synapse J. Immunol., August 1, 2008; 181(3): 1969 - 1977. [Abstract] [Full Text] [PDF]
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 L. Bertrand, S. Horman, C. Beauloye, and J.-L. Vanoverschelde Insulin signalling in the heart Cardiovasc Res, July 15, 2008; 79(2): 238 - 248. [Abstract] [Full Text] [PDF]
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J. Xing, Z. Zhang, H. Mao, R. G. Schnellmann, and S. Zhuang Src regulates cell cycle protein expression and renal epithelial cell proliferation via PI3K/Akt signaling-dependent and -independent mechanisms Am J Physiol Renal Physiol, July 1, 2008; 295(1): F145 - F152. [Abstract] [Full Text] [PDF]
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N. Thongon, L.-i. Nakkrasae, J. Thongbunchoo, N. Krishnamra, and N. Charoenphandhu Prolactin stimulates transepithelial calcium transport and modulates paracellular permselectivity in Caco-2 monolayer: mediation by PKC and ROCK pathways Am J Physiol Cell Physiol, May 1, 2008; 294(5): C1158 - C1168. [Abstract] [Full Text] [PDF]
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 A. M. Wolf, A. I. Lyuksyutova, A. G. Fenstermaker, B. Shafer, C. G. Lo, and Y. Zou Phosphatidylinositol-3-Kinase-Atypical Protein Kinase C Signaling Is Required for Wnt Attraction and Anterior-Posterior Axon Guidance J. Neurosci., March 26, 2008; 28(13): 3456 - 3467. [Abstract] [Full Text] [PDF]
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