title: Regulation of YAP by mechanical strain through Jnk and Hippo signaling.
abstract: 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.
authors.affiliation: Howard Hughes Medical Institute, Waksman Institute, and Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Veronica A
authors.initials: VA
authors.lastname: Codelia
authors.affiliation: Howard Hughes Medical Institute, Waksman Institute, and Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Gongping
authors.initials: G
authors.lastname: Sun
authors.affiliation: Howard Hughes Medical Institute, Waksman Institute, and Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA. Electronic address: irvine@waksman.rutgers.edu.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Irvine
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D001696:Biomechanical Phenomena; D002460:Cell Line; D049109:Cell Proliferation; D005260:Female; D000090683:Hippo Signaling Pathway; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D060588:LIM Domain Proteins / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; C403807:LIMD1 protein, human; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C092745:LATS1 protein, human; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases