Regulation of YAP by Mechanical Strain through Jnk and Hippo Signaling
Regulation of YAP by Mechanical Strain through Jnk and Hippo Signaling
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DOI：
10.1016/j.cub.2014.07.034
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发表时间：
2014-09-08
期刊：
影响因子：
9.2
通讯作者：
Irvine, Kenneth D.
中科院分区：
文献类型：
--
作者：
Codelia, Veronica A.;Sun, Gongping;Irvine, Kenneth D.
机械力影响我们身体的所有组织。主要在培养细胞上进行的实验已经确定，改变这些力会影响细胞行为，包括迁移、分化、凋亡和增殖[1，2]。转录辅激活因子雅普已被确定为机械信号的核中继，但导致雅普激活的分子机制尚未确定[3]。雅普是Hippo信号传导途径的主要转录效应子，Hippo信号传导途径是后生动物内的主要生长调节途径[4]，但至少在某些情况下，据报道机械应变对雅普的影响不依赖于Hippo信号传导[5，6]。在这里，我们确定了一个分子途径，可以促进培养的乳腺上皮细胞的增殖周期性或静态拉伸。这些机械刺激与转录辅激活因子雅普的活性增加有关，这至少部分是由于Hippo途径活性的抑制。这种对Hippo信号传导的影响大部分可以通过机械应变激活c-Jun N-末端激酶（JNK）活性和随后JNK抑制Hippo信号传导来解释。LATS 1是Hippo通路中雅普的关键负调节因子，我们进一步表明，循环拉伸与LATS抑制剂LIMD 1与LATS 1激酶结合的JNK依赖性增加相关，并且LIMD 1表达的减少抑制了循环拉伸对雅普的激活。总之，这些观察结果建立了通过JNK介导的Hippo信号传导抑制来机械调节细胞增殖的途径。
Mechanical forces affect all the tissues of our bodies. Experiments conducted mainly on cultured cells have established that altering these forces influences cell behaviors, including migration, differentiation, apoptosis, and proliferation [1, 2]. The transcriptional coactivator YAP has been identified as a nuclear relay of mechanical signals, but the molecular mechanisms that lead to YAP activation were not identified [3]. YAP is the main transcriptional effector of the Hippo signaling pathway, a major growth regulatory pathway within metazoa [4], but at least in some instances, the influence of mechanical strain on YAP was reported to be independent of Hippo signaling [5, 6]. Here, we identify a molecular pathway that can promote the proliferation of cultured mammary epithelial cells in response to cyclic or static stretch. These mechanical stimuli are associated with increased activity of the transcriptional coactivator YAP, which is due at least in part to inhibition of Hippo pathway activity. Much of this influence on Hippo signaling can be accounted for by the activation of c-Jun N-terminal kinase (JNK) activity by mechanical strain and subsequent inhibition of Hippo signaling by JNK. LATS1 is a key negative regulator of YAP within the Hippo pathway, and we further show that cyclic stretch is associated with a JNK-dependent increase in binding of a LATS inhibitor, LIMD1, to the LATS1 kinase and that reduction of LIMD1 expression suppresses the activation of YAP by cyclic stretch. Together, these observations establish a pathway for mechanical regulation of cell proliferation via JNK-mediated inhibition of Hippo signaling.