Merlin/NF-2 mediates contact inhibition of growth by suppressing recruitment of Rac to the plasma membrane.
Merlin/NF-2 mediates contact inhibition of growth by suppressing recruitment of Rac to the plasma membrane.
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DOI：
10.1083/jcb.200503165
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发表时间：
2005-10-24
期刊：
影响因子：
--
通讯作者：
Giancotti FG
中科院分区：
文献类型：
--
作者：
Okada T;Lopez-Lago M;Giancotti FG
引入活化的p21-激活的蛋白激酶(PAK)足以将原代内皮细胞从接触性生长抑制中释放出来。融合细胞显示PAK激活不足，RAC在基质粘连时移位到质膜。将RAC靶向质膜可以将这些细胞从接触抑制中解救出来。PAK释放人脐静脉内皮细胞接触抑制的能力被其靶标Merlin的非磷酸化形式阻断，这表明PAK通过磷酸化从而使Merlin失活来促进有丝分裂。Merlin突变体被认为发挥显性-负效应，使RAC能够重新募集到基质粘连并促进融合细胞的有丝分裂。小干扰RNA介导的Merlin基因敲除也发挥了同样的作用。显性负性RAC阻断PAK介导的接触抑制释放，暗示PAK在RAC上游的信号通路中起作用。这些结果为理解Merlin的肿瘤抑制功能提供了一个框架，并表明Merlin通过抑制RAC与基质粘连的募集而介导接触性生长抑制。
Introduction of activated p21-activated kinase (PAK) is sufficient to release primary endothelial cells from contact inhibition of growth. Confluent cells display deficient activation of PAK and translocation of Rac to the plasma membrane at matrix adhesions. Targeting Rac to the plasma membrane rescues these cells from contact inhibition. PAK's ability to release human umbilical vein endothelial cells from contact inhibition is blocked by an unphosphorylatable form of its target Merlin, suggesting that PAK promotes mitogenesis by phosphorylating, and thus inactivating, Merlin. Merlin mutants, which are presumed to exert a dominant-negative effect, enable recruitment of Rac to matrix adhesions and promote mitogenesis in confluent cells. Small interference RNA–mediated knockdown of Merlin exerts the same effects. Dominant-negative Rac blocks PAK-mediated release from contact inhibition, implying that PAK functions upstream of Rac in this signaling pathway. These results provide a framework for understanding the tumor suppressor function of Merlin and indicate that Merlin mediates contact inhibition of growth by suppressing recruitment of Rac to matrix adhesions.
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