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J. Biol. Chem., Vol. 279, Issue 31, 32786-32795, July 30, 2004

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Suppressors of T-cell Receptor Signaling Sts-1 and Sts-2 Bind to Cbl and Inhibit Endocytosis of Receptor Tyrosine Kinases^*

Katarzyna Kowanetz¶, Nicola Crosetto, Kaisa Haglund, Mirko H. H. Schmidt, Carl-Henrik Heldin, and Ivan Dikic||

From the Institute of Biochemistry II, Goethe University Medical School, 60590 Frankfurt, Germany, and Ludwig Institute for Cancer Research, SE-75 124 Uppsala, Sweden

The ubiquitin (Ub) ligase Cbl plays a critical role in attenuation of receptor tyrosine kinase (RTK) signaling by inducing ubiquitination of RTKs and promoting their sorting for endosomal degradation. Herein, we describe the identification of two novel Cbl-interacting proteins, p70 and Clip4 (recently assigned the names Sts-1 and Sts-2, respectively), that inhibit endocytosis of epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor. Sts-1 and Sts-2 contain SH3 domains that interacted with Cbl, Ub-associated domains, which bound directly to mono-Ub or to the EGFR/Ub chimera as well as phosphoglycerate mutase domains that mediated oligomerization of Sts-1/2. Ligand-induced recruitment of Sts-1/Sts-2 into activated EGFR complexes led to inhibition of receptor internalization, reduction in the number of EGFR-containing endocytic vesicles, and subsequent block of receptor degradation followed by prolonged activation of mitogenic signaling pathways. On the other hand, interference with Sts-1/Sts-2 functions diminished ligand-induced receptor degradation, cell proliferation, and oncogenic transformation in cultured fibroblasts. We suggest that Sts-1 and Sts-2 represent a novel class of Ub-binding proteins that regulate RTK endocytosis and control growth factor-induced cellular functions.

Received for publication, April 5, 2004 , and in revised form, May 19, 2004.

^* This work was supported by grants from the Boehringer Ingelheim Fonds, Deutsche Forschungsgemeinschaft, and Swedish Strategic Funds (to I. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Recipient of a Boehringer Ingelheim Fonds scholarship.

^|| To whom correspondence should be addressed: Theodor-Stern-Kai-7, Frankfurt 60590 Germany. Tel.: 49-69-6301-83647; Fax: 49-69-6301-5577; E-mail: ivan.dikic{at}biochem2.de.

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