PTEN inhibits PREX2-catalyzed activation of RAC1 to restrain tumor cell invasion.
PTEN inhibits PREX2-catalyzed activation of RAC1 to restrain tumor cell invasion.
复制标题
PTEN抑制RAC1的prex2催化活化以限制肿瘤细胞侵袭。
DOI：
10.1126/scisignal.2005840
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发表时间：
2015-03-31
影响因子：
7.3
通讯作者：
Parsons R
中科院分区：
文献类型：
--
作者：
Mense SM;Barrows D;Hodakoski C;Steinbach N;Schoenfeld D;Su W;Hopkins BD;Su T;Fine B;Hibshoosh H;Parsons R
肿瘤抑制因子PTEN通过一种独立于抑制PI3K通路和降低AKT激酶激活的机制来抑制细胞迁移和侵袭。PREX2是一种广泛分布的GEF，可激活GTPase RAC1，与PTEN结合并抑制PTEN。我们利用小鼠胚胎成纤维细胞和乳腺癌细胞系发现PTEN通过阻断PREX2活性来抑制细胞迁移和侵袭。除了代谢磷酸肌肽PIP3外，PTEN抑制prex2诱导的侵袭的机制需要PTEN的尾部结构域，而不需要其脂质磷酸酶活性。荧光核苷酸交换实验显示PTEN抑制PREX2对RAC1的GEF活性。PREX2是癌症中经常发生突变的GEF，对人类肿瘤数据的检查表明，PREX2突变与PTEN的高表达相关。因此，我们测试了癌源性体细胞PREX2突变体是否被PTEN抑制，这种突变体加速了永生化黑素细胞的肿瘤形成。我们测试的三个稳定表达的体细胞PREX2癌突变体对PTEN介导的侵袭抑制具有抗性，但保留了抑制PTEN脂质磷酸酶活性的能力。体外分析表明，PTEN不能阻断两个PREX2癌突变体的GEF活性，并且对第三个PREX2癌突变体的结合亲和力降低。因此，PTEN通过抑制PREX2 GEF活性来对抗迁移和侵袭，并且PREX2突变体可能在癌症中被选择以逃避PTEN介导的侵袭抑制。
The tumor suppressor PTEN restrains cell migration and invasion by a mechanism that is independent of inhibition of the PI3K pathway and decreased activation of the kinase AKT. PREX2, a widely distributed GEF that activates the GTPase RAC1, binds to and inhibits PTEN. We used mouse embryonic fibroblasts and breast cancer cell lines to show that PTEN suppresses cell migration and invasion by blocking PREX2 activity. In addition to metabolizing the phosphoinositide PIP3, PTEN inhibited PREX2-induced invasion by a mechanism that required the tail domain of PTEN, but not its lipid phosphatase activity. Fluorescent nucleotide exchange assays revealed that PTEN inhibited the GEF activity of PREX2 toward RAC1. PREX2 is a frequently mutated GEF in cancer, and examination of human tumor data showed that PREX2 mutation was associated with high PTEN expression. Therefore, we tested whether cancer-derived somatic PREX2 mutants, which accelerate tumor formation of immortalized melanocytes, were inhibited by PTEN. The three stably expressed, somatic PREX2 cancer mutants that we tested were resistant to PTEN-mediated inhibition of invasion but retained the ability to inhibit the lipid phosphatase activity of PTEN. In vitro analysis showed that PTEN did not block the GEF activity of two PREX2 cancer mutants and had a reduced binding affinity for the third. Thus, PTEN antagonized migration and invasion by restraining PREX2 GEF activity, and PREX2 mutants are likely selected in cancer to escape PTEN-mediated inhibition of invasion.