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doi: 10.1242/10.1242/jcs.00652

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Sprouty: how does the branch manager work?

Signal Transduction Laboratory, Institute of Molecular and Cell Biology, 30 Medical Drive, Singapore 117 609, Republic of Singapore

View larger version (67K): [in a new window]   Fig. 1. Conservation of key functional amino acids. When the various Spry proteins are aligned by the CLUSTAL program there are a number of sequences and single residues that are 100% conserved. The SpryTD and the Y55 conserved sequences are highlighted in green and orange, respectively. The triangle above the line denotes the conserved basic residue deemed necessary for binding to PtdIns(4,5)P2. Other than these regions that have been assigned crucial functions in Spry action there are several other isolated regions that are similarly conserved (depicted in blue or purple). Notably several of these are serine residues, which raises the question whether serine phosphorylation is important for Spry function.

View larger version (20K): [in a new window]   Fig. 2. A representation of the proteins that contain the conserved SpryTD together with associated domains.

View larger version (27K): [in a new window]   Fig. 3. An illustration of two functionally important domains on hSpry2 (and other Sprys) and the functions associated with them. The SpryTD (178-282) domain (gold) and the conserved tyrosine phosphorylation sequence (NXYXXXP) (blue). The residues highlighted in red are highly conserved residues that appear to be necessary for the tyrosine phosphorylation-dependent binding of c-Cbl to Spry proteins.

View larger version (18K): [in a new window]   Fig. 4. A suggested model for the hSpry2-induced abrogation of EGFR endocytosis. (A) Upon activation of EGFR, various tyrosine residues become phosphorylated on the cytosolic tail of the receptor and they become targets of both positive and negative regulatory proteins bearing intrinsic SH2 domains. Y1045 has the surrounding motif FLQRY(1045)SSDPT. The atypical SH2 domain on c-Cbl binds directly to Y1045. c-Cbl also functions as an E3 ubiquitin ligase where it `tags' certain target proteins for ubiquitylation, endocytosis and destruction via the intracellular endosomal system. In this case, c-Cbl accepts ubiquitin from an E2 ligase to enzymatically polyubiquitylate the EGFR, the first step in the downregulation process. A positive signal, by which the Ras/MAP-kinase pathway gets activated, is initiated by the binding of the Grb2 SH2 domain to tyrosine residues exemplified by Y1068. (B) When hSpry2 is expressed in activated cells it translocates to the plasma membrane, ostensibly by binding to free PtdIns(4,5)P2, and becomes phosphorylated on Y55, which is imbedded in a motif similar to that around Y1045 on the EGFR. The two tyrosine-phosphorylated sites on EGFR and hSpry2 therefore compete for binding to the SH2 domain of c-Cbl. Instead of EGFR downregulation it appears that the interaction of c-Cbl and hSpry leads to ubiquitylation and subsequent downregulation of hSpry2. The net result of this is the failure of EGFRs to submit to endocytosis and destruction, thus allowing the Ras/MAP-kinase signal to be sustained. (C) In the case of FGFR signaling there is a similar balance between Ras/MAP-kinase activation and signal inhibition. FGFRs require the constitutively associated docker protein FRS2 to provide the appropriate tyrosine-phosphorylated sites. There are four sites for Grb2 SH2-binding, represented by Y306, and two Shp2 SH2-binding sites, represented by Y436. The Ras/MAP-kinase signal is channeled mainly through the Shp2 pathway, whereas the directly bound Grb2 has associated c-Cbl that is capable of ubiquitylating both FGFRs and FRS2. (D) When Spry is expressed it translocates and binds to c-Cbl as described in B. The next part of the model becomes descriptive rather than mechanistic, whereby the Ras/MAP-kinase signal is inhibited possibly as a corollary of c-Cbl associating via its SH2 domain to Y55 of Spry.

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