title: Pi3kcb links Hippo-YAP and PI3K-AKT signaling pathways to promote cardiomyocyte proliferation and survival.
abstract: BACKGROUND
  Yes-associated protein (YAP), the nuclear effector of Hippo signaling, regulates cellular growth and survival in multiple organs, including the heart, by interacting with TEA (transcriptional enhancer activator)-domain sequence-specific DNA-binding proteins. Recent studies showed that YAP stimulates cardiomyocyte proliferation and survival. However, the direct transcriptional targets through which YAP exerts its effects are poorly defined.
  
  
  OBJECTIVE
  To identify direct YAP targets that mediate its mitogenic and antiapoptotic effects in the heart.
  
  
  RESULTS
  We identified direct YAP targets by combining differential gene expression analysis in YAP gain- and loss-of-function with genome-wide identification of YAP-bound loci using chromatin immunoprecipitation and high throughput sequencing. This screen identified Pik3cb, encoding p110β, a catalytic subunit of phosphoinositol-3-kinase, as a candidate YAP effector that promotes cardiomyocyte proliferation and survival. YAP and TEA-domain occupied a conserved enhancer within the first intron of Pik3cb, and this enhancer drove YAP-dependent reporter gene expression. Yap gain- and loss-of-function studies indicated that YAP is necessary and sufficient to activate the phosphoinositol-3-kinase-Akt pathway. Like Yap, Pik3cb gain-of-function stimulated cardiomyocyte proliferation, and Pik3cb knockdown dampened YAP mitogenic activity. Reciprocally, impaired heart function in Yap loss-of-function was significantly rescued by adeno-associated virus-mediated Pik3cb expression.
  
  
  CONCLUSIONS
  Pik3cb is a crucial direct target of YAP, through which the YAP activates phosphoinositol-3-kinase-AKT pathway and regulates cardiomyocyte proliferation and survival.
authors.affiliation: From the Department of Cardiology, Boston Children's Hospital, MA (Z.L., P.Z., A.v.G., F.G., Q.M., J.C., H.G., P.R.R.v.G., D.-Z.W., W.T.P.); Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical School, Hannover, Germany (A.v.G.); Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.G.); Department of Cardiology, Leiden University Medical Center, The Netherlands (P.R.R.v.G.); and Harvard Stem Cell Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.).
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Lin
authors.affiliation: From the Department of Cardiology, Boston Children's Hospital, MA (Z.L., P.Z., A.v.G., F.G., Q.M., J.C., H.G., P.R.R.v.G., D.-Z.W., W.T.P.); Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical School, Hannover, Germany (A.v.G.); Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.G.); Department of Cardiology, Leiden University Medical Center, The Netherlands (P.R.R.v.G.); and Harvard Stem Cell Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.).
authors.forename: Pingzhu
authors.initials: P
authors.lastname: Zhou
authors.affiliation: From the Department of Cardiology, Boston Children's Hospital, MA (Z.L., P.Z., A.v.G., F.G., Q.M., J.C., H.G., P.R.R.v.G., D.-Z.W., W.T.P.); Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical School, Hannover, Germany (A.v.G.); Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.G.); Department of Cardiology, Leiden University Medical Center, The Netherlands (P.R.R.v.G.); and Harvard Stem Cell Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.).
authors.forename: Alexander
authors.initials: A
authors.lastname: von Gise
authors.affiliation: From the Department of Cardiology, Boston Children's Hospital, MA (Z.L., P.Z., A.v.G., F.G., Q.M., J.C., H.G., P.R.R.v.G., D.-Z.W., W.T.P.); Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical School, Hannover, Germany (A.v.G.); Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.G.); Department of Cardiology, Leiden University Medical Center, The Netherlands (P.R.R.v.G.); and Harvard Stem Cell Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.).
authors.forename: Fei
authors.initials: F
authors.lastname: Gu
authors.affiliation: From the Department of Cardiology, Boston Children's Hospital, MA (Z.L., P.Z., A.v.G., F.G., Q.M., J.C., H.G., P.R.R.v.G., D.-Z.W., W.T.P.); Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical School, Hannover, Germany (A.v.G.); Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.G.); Department of Cardiology, Leiden University Medical Center, The Netherlands (P.R.R.v.G.); and Harvard Stem Cell Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.).
authors.forename: Qing
authors.initials: Q
authors.lastname: Ma
authors.affiliation: From the Department of Cardiology, Boston Children's Hospital, MA (Z.L., P.Z., A.v.G., F.G., Q.M., J.C., H.G., P.R.R.v.G., D.-Z.W., W.T.P.); Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical School, Hannover, Germany (A.v.G.); Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.G.); Department of Cardiology, Leiden University Medical Center, The Netherlands (P.R.R.v.G.); and Harvard Stem Cell Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.).
authors.forename: Jinghai
authors.initials: J
authors.lastname: Chen
authors.affiliation: From the Department of Cardiology, Boston Children's Hospital, MA (Z.L., P.Z., A.v.G., F.G., Q.M., J.C., H.G., P.R.R.v.G., D.-Z.W., W.T.P.); Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical School, Hannover, Germany (A.v.G.); Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.G.); Department of Cardiology, Leiden University Medical Center, The Netherlands (P.R.R.v.G.); and Harvard Stem Cell Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.).
authors.forename: Haidong
authors.initials: H
authors.lastname: Guo
authors.affiliation: From the Department of Cardiology, Boston Children's Hospital, MA (Z.L., P.Z., A.v.G., F.G., Q.M., J.C., H.G., P.R.R.v.G., D.-Z.W., W.T.P.); Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical School, Hannover, Germany (A.v.G.); Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.G.); Department of Cardiology, Leiden University Medical Center, The Netherlands (P.R.R.v.G.); and Harvard Stem Cell Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.).
authors.forename: Pim R R
authors.initials: PR
authors.lastname: van Gorp
authors.affiliation: From the Department of Cardiology, Boston Children's Hospital, MA (Z.L., P.Z., A.v.G., F.G., Q.M., J.C., H.G., P.R.R.v.G., D.-Z.W., W.T.P.); Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical School, Hannover, Germany (A.v.G.); Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.G.); Department of Cardiology, Leiden University Medical Center, The Netherlands (P.R.R.v.G.); and Harvard Stem Cell Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.).
authors.forename: Da-Zhi
authors.initials: DZ
authors.lastname: Wang
authors.affiliation: From the Department of Cardiology, Boston Children's Hospital, MA (Z.L., P.Z., A.v.G., F.G., Q.M., J.C., H.G., P.R.R.v.G., D.-Z.W., W.T.P.); Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical School, Hannover, Germany (A.v.G.); Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.G.); Department of Cardiology, Leiden University Medical Center, The Netherlands (P.R.R.v.G.); and Harvard Stem Cell Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.). wpu@enders.tch.harvard.edu.
authors.forename: William T
authors.initials: WT
authors.lastname: Pu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics; D001483:Base Sequence; D049109:Cell Proliferation / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000096:biosynthesis* / Q000235:genetics; D000090683:Hippo Signaling Pathway; D051379:Mice; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D000091102:YAP-Signaling Proteins
chemical_list: D051017:Apoptosis Regulatory Proteins; D000091102:YAP-Signaling Proteins; C509425:Yap1 protein, rat; D058544:Class Ib Phosphatidylinositol 3-Kinase; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: AAV; Akt; Hippo; PI3 kinase; Pik3cb; Yap; heart failure; regeneration