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PMID:12593796
| Citation |
Hall, AB, Jura, N, DaSilva, J, Jang, YJ, Gong, D and Bar-Sagi, D (2003) hSpry2 is targeted to the ubiquitin-dependent proteasome pathway by c-Cbl. Curr. Biol. 13:308-14 |
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| Abstract |
Sprouty was originally identified in a genetic screen in Drosophila as an antagonist of fibroblast (FGF) and epidermal growth factor (EGF) signaling. Subsequently, four vertebrate homologs were discovered; among these, the human homolog Sprouty 2 (hSpry2) contains the highest degree of sequence homology to the Drosophila protein. It has been shown that hSpry2 interacts directly with c-Cbl, an E3-ubiquitin ligase, which promotes the downregulation of receptor tyrosine kinases (RTKs). In this study, we have investigated the functional consequences of the association between hSpry2 and c-Cbl. We have found that hSpry2 is ubiquitinated by c-Cbl in an EGF-dependent manner. EGF stimulation induces the tyrosine phosphorylation of hSpry2, which in turn enhances the interaction of hSpry2 with c-Cbl. The c-Cbl-mediated ubiquitination of hSpry2 targets the protein for degradation by the 26S proteasome. An enhanced proteolytic degradation of hSpry2 is also observed in response to FGF stimulation. The FGF-induced degradation of hSpry2 limits the duration of the inhibitory effect of hSpry2 on extracellular signal-regulated kinase (ERK) activation and enables the cells to recover their sensitivity to FGF stimulation. Our results indicate that the interaction of hSpry2 with c-Cbl might serve as a mechanism for the downregulation of hSpry2 during receptor tyrosine kinase signaling. |
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| Keywords |
Animals; Cysteine Endopeptidases/metabolism; Humans; Multienzyme Complexes/metabolism; Nerve Tissue Proteins/metabolism; Phosphorylation; Proteasome Endopeptidase Complex; Proto-Oncogene Proteins/metabolism; Proto-Oncogene Proteins c-cbl; Tyrosine/metabolism; Ubiquitin/metabolism; Ubiquitin-Protein Ligases |
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Significance
Annotations
| Gene product | Qualifier | GO Term | Evidence Code | with/from | Aspect | Extension | Notes | Status |
|---|---|---|---|---|---|---|---|---|
| GO:0005886: plasma membrane |
EXP: Inferred from Experiment: : |
C |
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See also
References
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