When cells with excess DNA, such as tetraploid cells, undergo cell division, it can contribute to cellular transformation via asymmetrical chromosome segregation‐generated genetic diversity. Cell cycle progression of tetraploid cells is suppressed by large tumor suppressor 2 (LATS2) kinase‐induced inhibitory phosphorylation of the transcriptional coactivator Yes‐associated protein (YAP). We recently reported that the oncogene v‐Src induces tetraploidy and promotes cell cycle progression of tetraploid cells by suppressing LATS2 activity. We explore here the mechanism by which v‐Src suppresses LATS2 activity and the role of LATS2 in v‐Src‐expressing cells. LATS2 was directly phosphorylated by v‐Src and the proto‐oncogene c‐Src, resulting in decreased LATS2 kinase activity. This kinase‐deficient LATS2 accumulated in a YAP transcriptional activity‐dependent manner, and knockdown of either LATS2 or the LATS2‐binding partner moesin‐ezrin‐radixin‐like protein (Merlin) accelerated v‐Src‐induced membrane bleb formation. Upon v‐Src expression, the interaction of Merlin with LATS2 was increased possibly due to a decrease in Merlin phosphorylation at Ser518, the dephosphorylation of which is required for the open conformation of Merlin and interaction with LATS2. LATS2 was colocalized with Merlin at the plasma membrane in a manner that depends on the Merlin‐binding region of LATS2. The bleb formation in v‐Src‐expressing and LATS2‐knockdown cells was rescued by the reexpression of wild‐type or kinase‐dead LATS2 but not the LATS2 mutant lacking the Merlin‐binding region. These results suggest that the kinase‐deficient LATS2 plays a role with Merlin at the plasma membrane in the maintenance of cortical rigidity in v‐Src‐expressing cells, which may cause tumor suppression.

中文翻译：

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肿瘤抑制因子 LATS2 以激酶活性无关的方式减少 v-Src 诱导的膜泡

当具有过量 DNA 的细胞（如四倍体细胞）进行细胞分裂时，它可以通过不对称的染色体分离产生的遗传多样性促进细胞转化。四倍体细胞的细胞周期进程受到大肿瘤抑制因子 2 (LATS2) 激酶诱导的转录共激活因子 Yes 相关蛋白 (YAP) 的抑制性磷酸化的抑制。我们最近报道了癌基因 v-Src 通过抑制 LATS2 活性诱导四倍体细胞并促进四倍体细胞的细胞周期进程。我们在这里探讨了 v-Src 抑制 LATS2 活性的机制以及 LATS2 在表达 v-Src 的细胞中的作用。LATS2 被 v-Src 和原癌基因 c-Src 直接磷酸化，导致 LATS2 激酶活性降低。这种激酶缺陷的 LATS2 以 YAP 转录活性依赖的方式积累，敲除 LATS2 或 LATS2 结合伙伴 moesin-ezrin-radixin 样蛋白 (Merlin) 加速了 v-Src 诱导的膜泡形成。在 v-Src 表达后，Merlin 与 LATS2 的相互作用增加，可能是由于 Ser518 处 Merlin 磷酸化的减少，Merlin 的开放构象和与 LATS2 的相互作用需要去磷酸化。LATS2 与 Merlin 共定位于质膜，其方式取决于 LATS2 的 Merlin 结合区。表达 v-Src 和敲低 LATS2 的细胞中的泡形成可以通过重新表达野生型或激酶死亡的 LATS2 而不是缺乏 Merlin 结合区的 LATS2 突变体来拯救。