Regulation of YAP by Mechanical Strain through Jnk and Hippo Signaling

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. •Cyclic stretch activates YAP through downregulation of Hippo signaling•Cyclic stretch inhibits Hippo signaling through JNK activation•JNK activation inhibits Hippo signaling by increasing LIMD1-LATS1 binding•These observations delineate a biomechanical signaling pathway that regulates YAP Codelia et al. identify a biomechanical signaling pathway that activates the YAP transcription factor and promotes cell proliferation. Cyclic stretch activates YAP by inhibiting Hippo signaling. This occurs through activation of c-Jun N-terminal kinase by cyclic stretch, which then inhibits LATS by increasing its binding to the LATS inhibitor LIMD1.