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  • The EMBO Journal (2007) 26, 647 - 656
  • doi:10.1038/sj.emboj.7601534

Published online: 25 January 2007

CIN85, a Cbl-interacting protein, is a component of AMAP1-mediated breast cancer invasion machinery

Jin-Min Nam1,2, Yasuhito Onodera1,2, Yuichi Mazaki1, Hiroyuki Miyoshi3, Shigeru Hashimoto1 and Hisataka Sabe1,2

  1. Department of Molecular Biology, Osaka Bioscience Institute, Suita, Osaka, Japan
  2. Graduate School of Biostudies, Kyoto University, Kyoto, Japan
  3. Subteam for Manipulation of Cell Fate, BioResource Center, RIKEN Tsukuba Institute, Tsukuba, Japan

Correspondence to:

Hisataka Sabe, Department of Molecular Biology, Osaka Bioscience Institute, 6-2-4 Furuedai, Suita, Osaka 565-0874, Japan. Tel.: +81 6 6872 4814; Fax: +81 6 6871 6686; E-mail: sabe@obi.or.jp

Received 30 August 2006; Accepted 7 December 2006

Expression of AMAP1 correlates well with the invasive phenotypes and malignancy of human primary breast carcinomas. AMAP1 recruits its binding proteins, such as cortactin and paxillin, to sites of Arf6 activation to form invadopodia. A mouse ortholog of AMAP1, ASAP1, is known to bind to CIN85, a binding partner of an E3 ligase, Cbl. Here, we found that CIN85 colocalizes with AMAP1 at invadopodia, and binding of AMAP1 with CIN85 is important for the invasive activities of breast cancer cells, including MDA-MB-231. siRNA-mediated silencing of CIN85, as well as Cbl, also inhibited the invasion. We moreover found that AMAP1 is monoubiquitinated, rather than polyubiquitinated, by virtue of Cbl and provide evidence that the ability of AMAP1 to be monoubiquitinated is important for its involvement in invasion. Our results indicate that CIN85, as well as Cbl, which is a well-known suppressor of growth factor receptor signaling, can be positively involved in tumor invasion, and suggest that a complex epigenetic process is involved in AMAP1 function in breast cancer cell invasion.

  • Keywords:

    • AMAP1,
    • breast cancer,
    • invasion,
    • ubiquitination