STRIPAK components determine mode of cancer cell migration and metastasis.
STRIPAK components determine mode of cancer cell migration and metastasis.
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DOI：
10.1038/ncb3083
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发表时间：
2015-01
影响因子：
21.3
通讯作者：
Sahai E
中科院分区：
文献类型：
--
作者：
Madsen CD;Hooper S;Tozluoglu M;Bruckbauer A;Fletcher G;Erler JT;Bates PA;Thompson B;Sahai E
收缩性肌动球蛋白细胞骨架及其与质膜的连接对于控制细胞形状和迁移至关重要。我们确定了三个STRIPAK复合物组分，FAM 40 A，FAM 40 B和STRN 3，作为肌动球蛋白皮质的调节剂。我们表明，FAM 40 A负调节MST 3和MST 4激酶，这促进了收缩肌动球蛋白机制与Ezrin/Radixin/Moesin家族蛋白的共定位，通过磷酸化PPP 1CB，PPP 1 R14 A-D的抑制剂。使用计算模型，在体外细胞迁移试验和体内乳腺癌转移试验，我们证明，共定位的收缩活动和肌动蛋白质膜连接降低细胞的速度在平面表面上，但有利于在密闭环境中的迁移类似于在体内观察到的。我们进一步表明，在人类肿瘤中发现的FAM 40 B突变使其与PP 2A解偶联，并使其能够驱动收缩表型，这可能是其在人类癌症中作用的基础。
The contractile actomyosin cytoskeleton and its connection to the plasma membrane are critical for control of cell shape and migration. We identify three STRIPAK complex components, FAM40A, FAM40B, and STRN3, as regulators of the actomyosin cortex. We show that FAM40A negatively regulates the MST3 and MST4 kinases, which promote the co-localisation of the contractile actomyosin machinery with the Ezrin/Radixin/Moesin family proteins by phosphorylating the inhibitors of PPP1CB, PPP1R14A-D. Using computational modelling, in vitro cell migration assays and in vivo breast cancer metastasis assays we demonstrate that co-localisation of contractile activity and actin-plasma membrane linkage reduces cell speed on planar surfaces, but favours migration in confined environments similar to those observed in vivo. We further show that FAM40B mutations found in human tumours uncouple it from PP2A and enable it to drive a contractile phenotype, which may underlie its role in human cancer.