JNK phosphorylates Yes-associated protein (YAP) to regulate apoptosis
TLDR
It is shown that YAP protects keratinocytes from UV irradiation but promotes UV-induced apoptosis in a squamous cell carcinoma, and JNK specifically phosphorylates endogenous YAP in a number of cell types.Abstract:
Yes-associated protein (YAP) regulates DNA damage and chemosensitivity, as well as functioning as a pro-growth, cell size regulator. For both of its roles, regulation by phosphorylation is crucial. We undertook an in vitro screen to identify novel YAP kinases to discover new signaling pathways to better understand YAP's function. We identified JNK1 and JNK2 as robust YAP kinases, as well as mapped multiple sites of phosphorylation. Using inhibitors and siRNA, we showed that JNK specifically phosphorylates endogenous YAP in a number of cell types. We show that YAP protects keratinocytes from UV irradiation but promotes UV-induced apoptosis in a squamous cell carcinoma. We defined the mechanism for this dual role to be YAP's ability to bind and stabilize the pro-proliferative ΔNp63α isoform in a JNK-dependent manner. Our report indicates that an evaluation of the expression of the different isoforms of p63 and p73 is crucial in determining YAP's function.read more
Citations
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RASSF1A elicits apoptosis through an MST2 pathway directing proapoptotic transcription by the p73 tumor suppressor protein.
David Matallanas,David Romano,Karen Yee,Katrin Meissl,Lucia Kucerova,Daniela Piazzolla,Manuela Baccarini,J. Keith Vass,Walter Kolch,Eric O'Neill +9 more
TL;DR: It is shown that key steps in RASSF1A-induced apoptosis are the disruption of the inhibitory Raf1-MST2 complex by RASSf1A and the concomitant enhancement of MST2 interaction with its substrate, LATS1.
Journal ArticleDOI
JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships
TL;DR: Because upstream signaling components impact JNK activity, this work critically assessed the involvement of signaling scaffolds and the roles of feedback mechanisms in the JNK pathway.
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Downstream of Mutant KRAS, the Transcription Regulator YAP Is Essential for Neoplastic Progression to Pancreatic Ductal Adenocarcinoma
Weiying Zhang,Nivedita Nandakumar,Yuhao Shi,Mark Manzano,Alias Smith,Garrett T. Graham,Swati Gupta,Eveline E. Vietsch,Sean Z. Laughlin,Mandheer Wadhwa,Mahandranauth A. Chetram,Mrinmayi Joshi,Fen Wang,Bhaskar Kallakury,Jeffrey A. Toretsky,Anton Wellstein,Chunling Yi +16 more
TL;DR: Yap acted as a critical transcriptional switch downstream of the oncogenic KRAS–mitogen-activated protein kinase (MAPK) pathway, promoting the expression of genes encoding secretory factors that cumulatively sustained neoplastic proliferation, a tumorigenic stromal response in the tumor microenvironment, and PDAC progression in Kras and Kras:Trp53 mutant pancreas tissue.
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Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy.
Jonathan Pol,Erika Vacchelli,Fernando Aranda,Francesca Castoldi,Alexander M.M. Eggermont,Isabelle Cremer,Catherine Sautès-Fridman,Jitka Fucikova,Jérôme Galon,Radek Spisek,Eric Tartour,Laurence Zitvogel,Guido Kroemer,Lorenzo Galluzzi +13 more
TL;DR: Recent developments on anticancer chemotherapy based on ICD inducers are discussed, including the case of cardiac glycosides, like digoxin and digitoxin, and zoledronic acid.
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The Hippo pathway in intestinal regeneration and disease
TL;DR: This Review summarizes studies on the role of the Hippo pathway in the intestine on these physiological processes and the underlying mechanisms responsible, and discusses future research directions and potential therapeutic strategies targeting Hippo signalling in intestinal disease.
References
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Journal ArticleDOI
Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control
Bin Zhao,Xiaomu Wei,Weiquan Li,Ryan S. Udan,Ryan S. Udan,Qian Yang,Joungmok Kim,Joungmok Kim,Joe Xie,Tsuneo Ikenoue,Jindan Yu,Li Li,Li Li,Pan Zheng,Keqiang Ye,Arul M. Chinnaiyan,Georg Halder,Georg Halder,Zhi Chun Lai,Kun-Liang Guan,Kun-Liang Guan +20 more
TL;DR: It is demonstrated that in mammalian cells, the transcription coactivator YAP (Yes-associated protein), is inhibited by cell density via the Hippo pathway, and YAP overexpression regulates gene expression in a manner opposite to cell density, and is able to overcome cell contact inhibition.
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SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase
Brydon L. Bennett,Dennis T. Sasaki,Brion W. Murray,Eoin C. O'leary,Steve T. Sakata,Weiming Xu,Jim C. Leisten,Aparna Motiwala,Steve Pierce,Yoshitaka Satoh,Shripad S. Bhagwat,Anthony M. Manning,David W. Anderson +12 more
TL;DR: SP600125 blocked (bacterial) lipopolysaccharide-induced expression of tumor necrosis factor-α and inhibited anti-CD3-induced apoptosis of CD4+ CD8+ thymocytes and supports targeting JNK as an important strategy in inflammatory disease, apoptotic cell death, and cancer.
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SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1
Ana Cuenda,John Rouse,Yair N. Doza,Roger Meier,Philip Cohen,Timothy Francis Gallagher,Peter R. Young,John C. Lee +7 more
TL;DR: It is established that MAPKAP kinase‐2 is a physiological RK substrate, and that HSP27 is phosphorylated by MAPK AP kinase-2 in vivo.
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Elucidation of a universal size-control mechanism in Drosophila and mammals.
Jixin Dong,Georg Feldmann,Jianbin Huang,Shian Wu,Nailing Zhang,Sarah A. Comerford,Mariana F. Gayyed,Robert A. Anders,Anirban Maitra,Duojia Pan +9 more
TL;DR: It is demonstrated that a single phosphorylation site in Yki mediates the growth-suppressive output of the Hippo pathway, and that its dysregulation leads to tumorigenesis, uncovering a universal size-control mechanism in metazoan.
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TEAD mediates YAP-dependent gene induction and growth control
Bin Zhao,Xin Ye,Jindan Yu,Li Li,Li Li,Weiquan Li,Siming Li,Jianjun Yu,Jiandie D. Lin,Cun-Yu Wang,Arul M. Chinnaiyan,Zhi Chun Lai,Kun-Liang Guan +12 more
TL;DR: TEAD is revealed as a new component in the Hippo pathway playing essential roles in mediating biological functions of YAP, and is required for YAP-induced cell growth, oncogenic transformation, and epithelial-mesenchymal transition.