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© The Rockefeller University Press, 0021-9525/2003/3/804 $5.00
The Journal of Cell Biology, Volume 160, Number 6, 804-804

Inducing Sprouty degradation

EGF (lower panel) stimulates the association of hSpry2 (green) with c-Cbl (red) and hSpry2 degradation Bar-Sagi/Elsevier

Receptor tyrosine kinases are often regulated by negative feedback loops that limit their signaling duration. But cells then need to get out of that loop so that they can respond once again. One way to balance the scales is a "signal- dependent degradation of a negative regulator," according to Dafna Bar-Sagi.

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.

References:

Rubin, C., et al. 2003. Curr. Biol. 13:297–307.[CrossRef][Medline]

EGF (lower panel) stimulates the association of hSpry2 (green) with c-Cbl (red) and hSpry2 degradation.

Bar-Sagi/Elsevier

Hall, A., et al. 2003. Curr. Biol. 13:308–314.[CrossRef][Medline]

Nicole LeBrasseur

lebrasn{at}rockefeller.edu

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This Article Full Text (PDF, 837K) Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by LeBrasseur, N. Search for Related Content PubMed Articles by LeBrasseur, N. Social Bookmarking                            What's this?