title: Mst1 promotes cardiac myocyte apoptosis through phosphorylation and inhibition of Bcl-xL.
abstract: The Hippo pathway, evolutionarily conserved from flies to mammals, promotes cell death and inhibits cell proliferation to regulate organ size. The core component of this cascade, Mst1 in mammalian cells, is sufficient to promote apoptosis. However, the mechanisms underlying both its activation and its ability to elicit cell death remain largely undefined. We here identify a signaling cassette in cardiac myocytes consisting of K-Ras, the scaffold RASSF1A, and Mst1 that is localized to mitochondria and promotes Mst1 activation in response to oxidative stress. Activated Mst1 phosphorylates Bcl-xL at Ser14, which resides in the BH4 domain, thereby antagonizing Bcl-xL-Bax binding. This, in turn, causes activation of Bax and subsequent mitochondria-mediated apoptotic death. Our findings demonstrate mitochondrial localization of Hippo signaling and identify Bcl-xL as a target that is directly modified to promote apoptosis.
authors.affiliation: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Del Re
authors.affiliation: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Matsuda
authors.affiliation: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Peiyong
authors.initials: P
authors.lastname: Zhai
authors.affiliation: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Maejima
authors.affiliation: Center for Advanced Proteomics Research, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Mohit Raja
authors.initials: MR
authors.lastname: Jain
authors.affiliation: Center for Advanced Proteomics Research, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Tong
authors.initials: T
authors.lastname: Liu
authors.affiliation: Center for Advanced Proteomics Research, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Division of Cardiovascular Surgery, Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taipei, Taiwan, Republic of China.
authors.forename: Chiao-Po
authors.initials: CP
authors.lastname: Hsu
authors.affiliation: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ 07103, USA. Electronic address: sadoshju@njms.rutgers.edu.
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
mesh_terms: D000818:Animals; D017209:Apoptosis; D001665:Binding Sites / Q000235:genetics; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000502:physiology*; D018384:Oxidative Stress; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism; D000099317:Hippo Kinases
chemical_list: D017346:Protein Serine-Threonine Kinases; D012694:Serine; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D018631:ras Proteins; C494812:Bcl2l1 protein, mouse; C490660:Stk4 protein, mouse; D000099317:Hippo Kinases