The inducible degradation of the protein hSpry2, a human homologue of the negative regulator Sprouty, is the subject of two recent articles. In the fly, Sprouty is an antagonist of fibroblast and epidermal growth factor (FGF and EGF) signaling, whereas the human version inhibits only FGF signaling. Now, Amy Hall, Natalia Jura, Bar-Sagi, and colleagues (State University of New York, Stony Brook, NY) and Chanan Rubin, Yosef Yarden, and colleagues (Weizmann Institute, Rehovot, Israel) show that when EGF activates its receptor, it also triggers degradation of hSpry2.
Both groups demonstrated that EGF induced the phosphorylation of hSpry2—a modification that increased hSpry2's association with the ubiquitin ligase c-Cbl. Although ubiquitinated hSpry2 was then degraded by the proteasome, the transient EGF-induced recruitment of c-Cbl to hSpry2 prevented the ubiquitin ligase from associating with the EGF receptor (EGFR). Thus, hSpry2 delayed c-Cbl-mediated degradation of EGFR.
As hSpry inhibits FGF signaling, this pathway also got a boost from the interaction of hSpry2 and c-Cbl. Bar-Sagi's group found that growth factor–induced degradation of hSpry2 limited its duration as an inhibitor of FGF signaling and allowed cells to respond once again to FGF stimulation. Interference with the degradation of hSpry2 resulted in sustained inhibition of FGF signaling.
Although both stories highlight the inducible c-Cbl–regulated degradation of hSpry2, it is not clear how hSpry2 inhibits FGFR before hSpry2 is degraded, or why this activity is lost from the EGFR cascade in human cells. ▪
EGF (lower panel) stimulates the association of hSpry2 (green) with c-Cbl (red) and hSpry2 degradation.