Pi3kcb links Hippo-YAP and PI3K-AKT signaling pathways to promote cardiomyocyte proliferation and survival

Circ Res. 2015 Jan 2;116(1):35-45. doi: 10.1161/CIRCRESAHA.115.304457. Epub 2014 Sep 23.

Abstract

Rationale: 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.

Methods and 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.

Keywords: AAV; Akt; Hippo; PI3 kinase; Pik3cb; Yap; heart failure; regeneration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis Regulatory Proteins / biosynthesis*
  • Apoptosis Regulatory Proteins / genetics
  • Base Sequence
  • Cell Proliferation / physiology*
  • Cell Survival / physiology
  • Cells, Cultured
  • Class Ib Phosphatidylinositol 3-Kinase / biosynthesis*
  • Class Ib Phosphatidylinositol 3-Kinase / genetics
  • Mice
  • Molecular Sequence Data
  • Myocytes, Cardiac / physiology*
  • Protein-Serine-Threonine Kinases / biosynthesis*
  • Protein-Serine-Threonine Kinases / genetics
  • Proto-Oncogene Proteins c-akt / biosynthesis*
  • Proto-Oncogene Proteins c-akt / genetics
  • Rats
  • Signal Transduction / physiology

Substances

  • Apoptosis Regulatory Proteins
  • Yap1 protein, rat
  • Class Ib Phosphatidylinositol 3-Kinase
  • Hippo protein, mouse
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt