The interaction of p130Cas with PKN3 promotes malignant growth
The interaction of p130Cas with PKN3 promotes malignant growth
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DOI：
10.1002/1878-0261.12401
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发表时间：
2019-02-01
影响因子：
6.6
通讯作者：
Brabek, Jan
中科院分区：
文献类型：
--
作者：
Gemperle, Jakub;Dibus, Michal;Brabek, Jan
蛋白质p130 Cas构成主要参与Src激酶下游的整合素信号传导的衔接蛋白。由于其模块化结构，p130 Cas作为由不同癌基因诱导的癌细胞生长和侵袭的一般调节剂。然而，p130 Cas信号传导导致恶性进展的其他机制知之甚少。在这里，我们显示了一种新的相互作用p130 Cas与丝氨酸/苏氨酸激酶PKN 3，这是牵连在前列腺癌和乳腺癌的生长下游的磷酸肌醇3-激酶。这种直接相互作用是由p130 Cas SH 3结构域和位于中心的PKN 3聚脯氨酸序列介导的。PKN 3是第一个被鉴定的结合并磷酸化p130 Cas并与p130 Cas共定位在具有促侵袭功能的细胞结构中的Ser/Thr激酶。此外，PKN 3-p130 Cas的相互作用是重要的小鼠胚胎成纤维细胞的生长和侵袭力的Src转化独立，表明一种机制不同于先前的p130 Cas的特点。总之，我们的研究结果表明PKN 3-p130 Cas复合物是晚期恶性肿瘤的一个有吸引力的治疗靶点。
Protein p130Cas constitutes an adaptor protein mainly involved in integrin signaling downstream of Src kinase. Owing to its modular structure, p130Cas acts as a general regulator of cancer cell growth and invasiveness induced by different oncogenes. However, other mechanisms of p130Cas signaling leading to malignant progression are poorly understood. Here, we show a novel interaction of p130Cas with Ser/Thr kinase PKN3, which is implicated in prostate and breast cancer growth downstream of phosphoinositide 3-kinase. This direct interaction is mediated by the p130Cas SH3 domain and the centrally located PKN3 polyproline sequence. PKN3 is the first identified Ser/Thr kinase to bind and phosphorylate p130Cas and to colocalize with p130Cas in cell structures that have a pro-invasive function. Moreover, the PKN3-p130Cas interaction is important for mouse embryonic fibroblast growth and invasiveness independent of Src transformation, indicating a mechanism distinct from that previously characterized for p130Cas. Together, our results suggest that the PKN3-p130Cas complex represents an attractive therapeutic target in late-stage malignancies.