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This Article Accepted manuscript (PDF) Supplementaty table 1 All Versions of this Article: JOE-09-0110v1 JOE-09-0110v2 203/2/191    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Guy, G Articles by Chow, S Y Search for Related Content PubMed PubMed Citation Articles by Guy, G Articles by Chow, S Y

G Guy, Institute of Molecular and Cell Biology, Proteos, Singapore
R Jackson, Institute of Molecular and Cell Biology, Proteos, Singapore
P Yusoff, Institute of Molecular and Cell Biology, Proteos, Singapore
S Chow, Institute of Molecular and Cell Biology, Proteos, Singapore

Correspondence: G Guy, Email: mcbgg{at}imcb.a-star.edu.sg

Sprouty proteins are involved in organogenesis, particularly during the branching of endothelial tubes, and existing evidence suggests that Sprouty’s point of action lies downstream of receptor signaling to inhibit the activation of the central Ras/Erk pathway. How Sprouty proteins accomplish their inhibitory action and whether they interact with other signaling pathways are significant questions. Sprouty proteins are devoid of any recognizable protein interaction domain, and clues as to how they function have been mainly derived from screening for interacting partners. Conserved across all of the Sprouty proteins are 3 sequences: a Cbl-TKB binding motif centered on an obligatorily phosphorylated tyrosine (Y55 in Sprouty 2), a serine-rich motif and a cysteine-rich domain.

With the exception of a handful of proteins that bind to the N-terminus, most of the binding to Sprouty occurs via the cysteine-rich domain, predominantly by serine/threonine kinases that target sites within the serine-rich motif on Sprouty. Some of the resultant increase in phosphorylation is opposed by activated PP2A that binds to the N-terminal Cbl-TKB binding motif. Significantly, two ubiquitin E3 ligases also bind to the N-terminus of Sprouty: c-Cbl binds with high affinity to the TKB binding motif and SIAH2 binds constitutively to a different site: both proteins are able to direct the ubiquitination of Sprouty proteins and its destruction. The collective evidence points to Sprouty proteins as being substantially covalently-modified to control its location, stability, association and destruction. With such stringent control of the Sproutys, the main question is what key proteins does this facilitator bring together?