Editors' ChoiceGrowth Factor Signaling

Controlling Sprouty Activity

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Science's STKE  04 May 2004:
Vol. 2004, Issue 231, pp. tw157-TW157
DOI: 10.1126/stke.2312004TW157

Ligand binding to a receptor tyrosine kinase triggers cascades of intracellular signaling events that regulate numerous cellular processes, such as cell growth and proliferation. To ensure a normal response to growth factors, other proteins are enlisted to limit signaling pathway activity. For example, the conserved membrane-associated protein Sprouty (Spry) antagonizes signaling from various receptor tyrosine kinases by blocking the Ras to extracellular signal-regulated kinase (ERK) pathway. But growth factors also stimulate Spry expression, placing the inhibitor in a negative feedback loop. The circuitry involving Spry is even more complex, as Spry also interacts with other Spry proteins, with receptor-associated adaptor proteins Grb2 and FRS2, and with c-Cbl, an E3-type ubiquitin ligase. Mason et al. report that Spry2 becomes phosphorylated on a conserved tyrosine residue when mammalian fibroblasts are treated with fibroblast growth factor (FGF) or epidermal growth factor (EGF). This modification was necessary for Spry2 to shut down receptor activity. Cells expressing a mutated form of Spry2 lacking the critical tyrosine residue exhibited enhanced ERK activation in response to FGF and EGF. The mutation did not alter membrane localization of Spry2 or its ability to bind to other Spry or adaptor proteins in response to growth factors. However, the mutant was unable to associate with c-Cbl. In the absence of c-Cbl, efficient inhibition of receptor signaling to ERK in response to FGF was observed, indicating that Spry2 does not need to interact with c-Cbl to block receptor signaling. Rather, mutant Spry2 was insensitive to c-Cbl-mediated ubiquitination, indicating that the abundance of Spry2 is likely controlled by c-Cbl. Pharmacologic inhibitors suggest that phosphorylation of Spry2 requires a Src-family kinase. The authors suggest that tyrosine phosphorylation may allow Spry2 to associate with cofactors forming a complex that shuts down receptor signaling to ERK. Proteasomal degradation of Spry2, mediated by c-Cbl, may be a homeostatic control mechanism that is essential for maintaining the positive and negative feedback loops of growth factor receptor signaling circuits.

J. M. Mason, D. J. Morrison, B. Bassit, M. Dimri, H. Band, J. D. Licht, I. Gross, Tyrosine phosphorylation of sprouty proteins regulates their ability to inhibit growth factor signaling: A dual feedback loop. Mol. Biol. Cell 15, 2176-2188 (2004). [Abstract] [Full Text]

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