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J. Biol. Chem., Vol. 281, Issue 39, 28919-28931, September 29, 2006

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CFBP Is a Novel Tyrosine-phosphorylated Protein That Might Function as a Regulator of CIN85/CD2AP^*

Hiroaki Konishi¹, Kyoko Tashiro, Yasunobu Murata², Hiromi Nabeshi, Emiko Yamauchi, and Hisaaki Taniguchi

From the Institute for Enzyme Research, University of Tokushima, Tokushima 770-8503, Japan and Harima Institute at SPring-8, RIKEN, Hyogo 679-5148, Japan

To decipher the global network of the epidermal growth factor (EGF) receptor-mediated signaling pathway, a large scale proteomic analysis of tyrosine-phosphorylated proteins was conducted. Here, we focus on characterizing a novel protein, CFBP (CIN85/CD2AP family binding protein), identified in the study. CFBP was found to be phosphorylated at tyrosine 204 upon EGF stimulation, and the CIN85/CD2AP family was identified as a binding partner. A proline-rich motif of CFBP is recognized by one of the three Src-homology 3 domains of CIN85/CD2AP, and the affinity of the interaction is regulated by the tyrosine phosphorylation of CFBP. They co-localize in actinenriched structures, and overexpression of CFBP induced morphological changes with actin reorganization. Furthermore, CFBP accelerated the EGF receptor's down-regulation by facilitating the recruitment of Cbl to the CD2AP/CIN85 complex. Two spliced variants of CFBP lacking either exon 5 or 8 are also expressed, and the variant lacking exon 5 without the proline-rich motif lacks the ability to bind to the CIN85/CD2AP family. The CFBP protein seems to play a key role in the ligand-mediated internalization and down-regulation of the EGF receptor.

Received for publication, June 14, 2006 , and in revised form, July 17, 2006.

^* This work was supported in part by grants-in-aid for scientific research and by the Knowledge Cluster Initiative from the Ministry of Education, Culture, Sports, Science and Technology of Japan. 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.

² Present address: Dept. of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan.

¹ To whom correspondence should be addressed: Institute for Enzyme Research, University of Tokushima, 3-18-15 Kuramoto, Tokushima 770-8503, Japan. Tel.: 81-88-633-7427; Fax: 81-88-633-7428; E-mail: konishi{at}ier.tokushima-u.ac.jp.

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