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J. Biol. Chem., Vol. 281, Issue 51, 39152-39158, December 22, 2006

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Alix Facilitates the Interaction between c-Cbl and Platelet-derived Growth Factor -Receptor and Thereby Modulates Receptor Down-regulation^*

From the Ludwig Institute for Cancer Research, Uppsala University, Biomedical Center, SE-751 24 Uppsala, Sweden

Alix (ALG-2-interacting protein X) is an adaptor protein involved in down-regulation and sorting of cell surface receptors through the endosomal compartments toward the lysosome. In this study, we show that Alix interacts with the C-terminal region of the platelet-derived growth factor (PDGF) -receptor (PDGFR) and becomes transiently tyrosine-phosphorylated in response to PDGF-BB stimulation. Increased expression levels of Alix resulted in a reduced rate of PDGFR removal from the cell surface following receptor activation, and this was associated with decreased receptor degradation. Furthermore, Alix was found to co-immunoprecipitate with the ubiquitin ligase c-Cbl, and elevated Alix levels increased the interaction between c-Cbl and PDGFR. Interestingly, Alix interacted constitutively with both c-Cbl and PDGFR. Moreover, c-Cbl was found to be hyperphosphorylated in cells engineered to overexpress Alix compared with control cells. The increased c-Cbl phosphorylation correlated with enhanced proteasomal degradation of c-Cbl, which in turn correlated with a decreased ubiquitination of PDGFR. Our data suggest that Alix inhibits down-regulation of PDGFR by modulating the interaction between c-Cbl and the receptor, thereby affecting the ubiquitination of the receptor.

Received for publication, September 5, 2006 , and in revised form, November 2, 2006.

^* This work was supported by grants from the Swedish Research Council, Åke Wibergs stiftelse, Magnus Bergvalls stiftelse, and the ENDOTRACK integrated European Union project. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ To whom correspondence should be addressed: Ludwig Inst. for Cancer Research, Box 595, Biomedical Center, SE-751 24, Uppsala, Sweden. Tel.: 46-18-160406; Fax: 46-18-160420; E-mail: Johan.Lennartsson{at}LICR.uu.se.

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