Adhesion to fibronectin regulates Hippo signaling via the FAK-Src-PI3K pathway.
Adhesion to fibronectin regulates Hippo signaling via the FAK-Src-PI3K pathway.
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DOI：
10.1083/jcb.201501025
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发表时间：
2015-08-03
期刊：
影响因子：
--
通讯作者：
Gumbiner BM
中科院分区：
文献类型：
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作者：
Kim NG;Gumbiner BM
黏着斑激酶（FAK）-Src-PI3 K是Hippo通路的上游调控分支，以Lats依赖的方式刺激雅普的活性和核定位。Hippo通路参与调节增殖的接触抑制和对各种物理和化学刺激的反应。最近，已经鉴定了几种Hippo信号传导的上游负调节剂，包括表皮生长因子受体配体和溶血磷脂酸。我们发现，纤连蛋白粘附刺激粘着斑激酶（FAK）-Src信号是另一个上游负调节Hippo途径。在低细胞密度下接种的MCF-10A细胞中，FAK或Src的抑制以大肿瘤抑制同源物（Lats）依赖性方式阻止了Yes相关蛋白（雅普）的活化。血清饥饿的MCF-10A细胞与纤连蛋白的连接，而不是与聚-d-赖氨酸或层粘连蛋白的连接，通过FAK-Src-磷脂酰肌醇4，5-二磷酸3-激酶（PI3 K）信号通路诱导雅普核积聚。FAK、Src、PI3K或PDK 1活性的减弱阻断了由粘附至纤连蛋白刺激的雅普核积聚。这种通过纤连蛋白粘附信号传导的Hippo通路的负调节至少可以部分地解释细胞铺展对雅普核定位的影响，并且代表了对细胞粘附的响应的Lats依赖性组分。
Fibronectin adhesion stimulation of focal adhesion kinase (FAK)–Src–PI3K is an upstream regulatory branch of the Hippo pathway and stimulates the activity and nuclear localization of YAP in a Lats-dependent manner. The Hippo pathway is involved in the regulation of contact inhibition of proliferation and responses to various physical and chemical stimuli. Recently, several upstream negative regulators of Hippo signaling, including epidermal growth factor receptor ligands and lysophosphatidic acid, have been identified. We show that fibronectin adhesion stimulation of focal adhesion kinase (FAK)-Src signaling is another upstream negative regulator of the Hippo pathway. Inhibition of FAK or Src in MCF-10A cells plated at low cell density prevented the activation of Yes-associated protein (YAP) in a large tumor suppressor homologue (Lats)–dependent manner. Attachment of serum-starved MCF-10A cells to fibronectin, but not poly-d-lysine or laminin, induced YAP nuclear accumulation via the FAK–Src–phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) signaling pathway. Attenuation of FAK, Src, PI3K, or PDK1 activity blocked YAP nuclear accumulation stimulated by adhesion to fibronectin. This negative regulation of the Hippo pathway by fibronectin adhesion signaling can, at least in part, explain the effects of cell spreading on YAP nuclear localization and represents a Lats-dependent component of the response to cell adhesion.