Pi3kcb Links Hippo-YAP and PI3K-AKT Signaling Pathways to Promote Cardiomyocyte Proliferation and Survival

Abstract

Rationale YAP, the nuclear effector of Hippo signaling, regulates cellular growth and survival in multiple organs, including the heart, by interacting with TEAD 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 anti-apoptotic 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 (PI3K), as a candidate YAP effector that promotes cardiomyocyte proliferation and survival. YAP and TEAD 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 PI3K-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 AAV-mediated Pik3cb expression. Conclusion : Pik3cb is a crucial direct target of YAP, through which the YAP activates PI3K-AKTpathway and regulates cardiomyocyte proliferation and survival.

Adaptor proteins NUMB and NUMBL promote cell cycle withdrawal by targeting ERBB2 for degradation

“…Increased phosphorylation of STAT5 results in nuclear retention (48), and therefore interaction of pSTAT5 with YAP1 would be expected to result in nuclear retention of YAP1. Intriguingly, recent ChIP studies for YAP1 in a cardiomyocyte cell line indicated significant enrichment for STAT5-binding sites within the vicinity of YAP1-bound sites (49).…”

Hippo-mediated suppression of IRS2/AKT signaling prevents hepatic steatosis and liver cancer

“…Previous studies have suggested that YAP regulates components of the AKT pathway (i.e., PI3K, PTEN, and AKT) and that the Drosophila Hippo ortholog MST1 binds and inhibits AKT directly (26)(27)(28)(29). Increased YAP expression in human liver tumors is associated with high levels of p- AKT (30,31).…”

“…In mice, liverspecific knockout of the Hippo pathway components MST1/2, SAV1, or NF2 induces the expansion of hepatic progenitor cells via YAP/TAZ activation and leads eventually to the development of liver cancer (HCC, cholangiocarcinoma [CC], or both) (22)(23)(24)(25). Despite its importance in tumorigenesis, the role of Hippo signaling in the metabolic dysregulation that precedes the development of liver cancer remains unclear.Previous studies have suggested that YAP regulates components of the AKT pathway (i.e., PI3K, PTEN, and AKT) and that the Drosophila Hippo ortholog MST1 binds and inhibits AKT directly (26)(27)(28)(29). Increased YAP expression in human liver tumors is associated with high levels of p- AKT (30,31).…”

Newt cells secrete extracellular vesicles with therapeutic bioactivity in mammalian cardiomyocytes

“…A significance threshold was set at the commonly used values of ±1.3. Activation of the PI3K/AKT pathway, which is known to promote both cardiomyocyte proliferation and survival (Figure 3(a)) [38], peaked at 12 h and subsided 24 h after A1-CM exposure (Figure 3(b)). Conversely, there was a significant reduction in the expression of genes associated with cellular differentiation, including bone morphogenetic protein (BMP) signalling ( Z  = −1.13) and TGF-β signalling ( Z  = −1.89) pathways [39].…”