CIN85, a Cbl-interacting protein, is a component of AMAP1-mediated breast cancer invasion machinery
CIN85, a Cbl-interacting protein, is a component of AMAP1-mediated breast cancer invasion machinery
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DOI：
10.1038/sj.emboj.7601534
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发表时间：
2007-02-07
期刊：
影响因子：
11.4
通讯作者：
Sabe, Hisataka
中科院分区：
文献类型：
--
作者：
Nam, Jin-Min;Onodera, Yasuhito;Sabe, Hisataka
AMAP 1的表达与乳腺癌的浸润表型和恶性程度密切相关。AMAP 1将其结合蛋白，如coreplatin和桩蛋白，募集到Arf 6激活位点以形成侵入伪足。已知AMAP 1的小鼠直系同源物ASAP 1与CIN 85结合，CIN 85是E3连接酶Cbl的结合配偶体。在这里，我们发现CIN 85与AMAP 1共定位于侵袭伪足，并且AMAP 1与CIN 85的结合对于乳腺癌细胞（包括MDA-MB-231）的侵袭活性是重要的。siRNA介导的CIN 85沉默以及Cbl也抑制了侵袭。我们还发现，AMAP 1是monoubiquitinated，而不是polyubiquitinated，凭借Cbl和提供的证据表明，AMAP 1的能力是monoubiquitinated是重要的，它参与入侵。我们的研究结果表明，CIN 85，以及Cbl，这是一个众所周知的生长因子受体信号转导抑制剂，可以积极参与肿瘤的侵袭，并表明一个复杂的表观遗传过程中涉及AMAP 1功能在乳腺癌细胞的侵袭。
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.