Structural basis for the transforming activity of human cancer-related signaling adaptor protein CRK
Structural basis for the transforming activity of human cancer-related signaling adaptor protein CRK
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DOI：
10.1038/nsmb1241
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发表时间：
2007-06-01
影响因子：
16.8
通讯作者：
Inagaki, Fuyuhiko
中科院分区：
文献类型：
--
作者：
Kobashigawa, Yoshihiro;Sakai, Mieko;Inagaki, Fuyuhiko
CRKI（SH 2-SH 3）和CRKII（SH 2-SH 3-SH 3）是癌蛋白CRK的剪接同种型，其通过将酪氨酸激酶连接到小G蛋白来调节转录和细胞骨架重组以用于细胞生长和运动。CRKI显示出显著的转化活性，而CRKII的活性低，并且磷酸化的CRKII没有任何生物活性。CRK蛋白不同生物活性的分子机制仍然难以捉摸。我们通过NMR确定了CRKI，CRKII和磷酸化CRKII的溶液结构，并确定了产生其活性的分子机制。使用啮齿动物3 Y1成纤维细胞的突变分析结果与结构研究结果一致。总之，这些数据表明，接头区调节CRKII与其靶标的结合，从而调节细胞生长和运动性。
CRKI (SH2-SH3) and CRKII (SH2-SH3-SH3) are splicing isoforms of the oncoprotein CRK that regulate transcription and cytoskeletal reorganization for cell growth and motility by linking tyrosine kinases to small G proteins. CRKI shows substantial transforming activity, whereas the activity of CRKII is low, and phosphorylated CRKII has no biological activity whatsoever. The molecular mechanisms underlying the distinct biological activities of the CRK proteins remain elusive. We determined the solution structures of CRKI, CRKII and phosphorylated CRKII by NMR and identified the molecular mechanism that gives rise to their activities. Results from mutational analysis using rodent 3Y1 fibroblasts were consistent with those from the structural studies. Together, these data suggest that the linker region modulates the binding of CRKII to its targets, thus regulating cell growth and motility.