hSpry2 Is Targeted to the Ubiquitin-Dependent Proteasome Pathway by c-Cbl

Sprouty was originally identified in a genetic screen in Drosophila as an antagonist of fibroblast (FGF) and epidermal growth factor (EGF) signaling [1, 2]. Subsequently, four vertebrate homologs were discovered; among these, the human homolog Sprouty 2 (hSpry2) contains the highest degree of sequen...

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Bibliographic Details
Published in:Current biology 2003-02, Vol.13 (4), p.308-314
Main Authors: Hall, Amy B., Jura, Natalia, DaSilva, John, Jang, Yeon Joo, Gong, Delquin, Bar-Sagi, Dafna
Format: Article
Language:English
Subjects:
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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Summary:Sprouty was originally identified in a genetic screen in Drosophila as an antagonist of fibroblast (FGF) and epidermal growth factor (EGF) signaling [1, 2]. 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 [3, 4]. It has been shown that hSpry2 interacts directly with c-Cbl, an E3-ubiquitin ligase, which promotes the downregulation of receptor tyrosine kinases (RTKs) [5]. 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.
ISSN:0960-9822
1879-0445
DOI:10.1016/S0960-9822(03)00086-1