β1整合素依赖性Rac / I组PAK信号传导通过NF2 / Merlin介导Yes相关蛋白1（YAP1）的YAP活化。,Journal of Biological Chemistry

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β1整合素依赖性Rac / I组PAK信号传导通过NF2 / Merlin介导Yes相关蛋白1（YAP1）的YAP活化。
Journal of Biological Chemistry ( IF 4.0 ) Pub Date : 2017-10-04 , DOI: 10.1074/jbc.m117.808063
Hiba Sabra ₁ , Molly Brunner ₁ , Vinay Mandati ₂ , Bernhard Wehrle-Haller ₃ , Dominique Lallemand ₄ , Anne-Sophie Ribba ₁ , Genevieve Chevalier ₁ , Philippe Guardiola ₅ , Marc R Block ₁ , Daniel Bouvard ₆

Affiliation

细胞粘附至细胞外基质或粘附至周围细胞在细胞增殖和分化中起关键作用，并且对于适当的组织动态平衡至关重要。粘附依赖性细胞增殖的重要途径是Hippo信号级联，其由转录因子Yes相关蛋白1（YAP1）和具有PDZ结合基序（TAZ）的转录共激活因子共同调控。然而，细胞如何在分子水平上整合细胞外信息以调节YAP1的核定位仍然令人费解。本文中，我们研究了β1整合素在调节此过程中的作用。我们发现，β1整合素依赖性细胞粘附对于支持体内和体外间充质细胞的细胞增殖至关重要，β1整合素依赖性细胞粘附依赖于YAP1的磷酸化状态下调后介导的YAP1向细胞核的重新定位。大肿瘤抑制基因1和2（LATS1 / 2）。我们还发现，该表型依赖于小GTPase RAC1在质膜上的β1整合素依赖性局部活化来控制第1组的P21（RAC1）活化激酶（PAK）的活性。我们进一步报道了调节蛋白merlin （神经纤维蛋白2，NF2）分别通过其C末端部分和FERM结构域与YAP1和LATS1 / 2相互作用。PAK1介导的Ser-518上的Merlin磷酸化减少了Merlin与LATS1 / 2和YAP1的相互作用，导致YAP1脱磷酸化和核穿梭。我们的结果强调了RAC / PAK1是细胞粘附引发的YAP1调控的主要参与者。

"点击查看英文标题和摘要"

β1 integrin-dependent Rac/group I PAK signaling mediates YAP activation of Yes-associated protein 1 (YAP1) via NF2/merlin.

Cell adhesion to the extracellular matrix or to surrounding cells plays a key role in cell proliferation and differentiation and is critical for proper tissue homeostasis. An important pathway in adhesion-dependent cell proliferation is the Hippo signaling cascade, which is coregulated by the transcription factors Yes-associated protein 1 (YAP1) and transcriptional coactivator with PDZ-binding motif (TAZ). However, how cells integrate extracellular information at the molecular level to regulate YAP1's nuclear localization is still puzzling. Herein, we investigated the role of β1 integrins in regulating this process. We found that β1 integrin-dependent cell adhesion is critical for supporting cell proliferation in mesenchymal cells both in vivo and in vitro β1 integrin-dependent cell adhesion relied on the relocation of YAP1 to the nucleus after the down-regulation of its phosphorylated state mediated by large tumor suppressor gene 1 and 2 (LATS1/2). We also found that this phenotype relies on β1 integrin-dependent local activation of the small GTPase RAC1 at the plasma membrane to control the activity of P21 (RAC1)-activated kinase (PAK) of group 1. We further report that the regulatory protein merlin (neurofibromin 2, NF2) interacts with both YAP1 and LATS1/2 via its C-terminal moiety and FERM domain, respectively. PAK1-mediated merlin phosphorylation on Ser-518 reduced merlin's interactions with both LATS1/2 and YAP1, resulting in YAP1 dephosphorylation and nuclear shuttling. Our results highlight RAC/PAK1 as major players in YAP1 regulation triggered by cell adhesion.

更新日期：2019-11-01

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