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

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

Author information

1
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.).
2
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.

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

PMID:
25249570
PMCID:
PMC4282610
DOI:
10.1161/CIRCRESAHA.115.304457
[Indexed for MEDLINE]
Free PMC Article

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