Association of PTP-PEST with the SH3 domain of p130(cas); a novel mechanism of protein tyrosine phosphatase substrate recognition
Association of PTP-PEST with the SH3 domain of p130(cas); a novel mechanism of protein tyrosine phosphatase substrate recognition
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DOI：
10.1038/sj.onc.1201279
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发表时间：
1997-08-21
期刊：
影响因子：
8
通讯作者：
Tonks, NK
中科院分区：
文献类型：
--
作者：
Garton, AJ;Burnham, MR;Tonks, NK
蛋白酪氨酸磷酸酶PTP-PEST在体外和体内对p130（cas）表现出显著的底物特异性，p130（cas）是一种参与有丝分裂信号传导、细胞粘附诱导信号传导和多种癌基因转化的信号传导介质。我们发现p130（cas）的SH3结构域与PTP-PEST c端段富含脯氨酸的序列（PPPKPPR -P-335）之间存在高度亲和的相互作用。该序列中的脯氨酸337突变为丙氨酸，会显著削弱PTP-PEST识别酪氨酸磷酸化的p130（cas）作为底物的能力，但不会从质量上影响相互作用的选择性。因此，PTP-PEST和p130（cas）之间相互作用的高度特异性似乎是两种不同底物识别机制的结合；PTP-PEST的催化结构域有助于与p130（cas）相互作用的特异性，而SH3结构域介导的p130（cas）与PTP-PEST的关联显著提高了相互作用的效率。此外，我们的研究结果表明，p130(cas) SH3结构域的一个重要功能是与PTP-PEST结合，从而促进p130（cas）的去磷酸化，导致p130（cas）下游酪氨酸磷酸化依赖的信号事件终止。
The protein tyrosine phosphatase PTP-PEST displays remarkable substrate specificity, in vitro and in vivo for p130(cas) a signalling intermediate implicated in mitogenic signalling, cell-adhesion induced signalling, and in transformation by a variety of oncogenes. We have identified a high affinity interaction between the SH3 domain of p130(cas) and a proline-rich sequence ((PPPKPPR)-P-335) within the C-terminal segment of PTP-PEST. Mutation of proline 337 within this sequence to alanine significantly impairs the ability of PTP-PEST to recognise tyrosine phosphorylated p130(cas) as a substrate, without qualitatively affecting the selectivity of the interaction. Thus the highly specific nature of the interaction between PTP-PEST and p130(cas) appears to result from a combination of two distinct substrate recognition mechanisms; the catalytic domain of PTP-PEST contributes specificity to the interaction with p130(cas), whereas the SH3 domain-mediated association of p130(cas) and PTP-PEST dramatically increases the efficiency of the interaction. Furthermore, our results indicate that one important function of the p130(cas) SH3 domain is to associate with PTP-PEST and thereby facilitate the dephosphorylation of p130(cas), resulting in the termination of tyrosine phosphorylation-dependent signalling events downstream of p130(cas).