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Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Curr+Biol 2014 ; 24 (17): 2012-7 Nephropedia Template TP
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Regulation of YAP by Mechanical Strain through Jnk and Hippo Signaling #MMPMID25127217
Codelia VA; Sun G; Irvine KD
Curr Biol 2014[Sep]; 24 (17): 2012-7 PMID25127217show ga
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 co-activator 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 were 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 co-activator 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.