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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