NIH Research Festival
Yes-associated protein (YAP) is the main transcriptional coactivator of the Hippo pathway, which regulates organ size, tissue homeostasis, and regeneration. YAP integrates multiple inputs from different signaling cascades. Recent evidence implicates YAP also in the control of nutrient and energy status of the cell, but the underlying mechanisms are unclear. In this study, we show that insulin modulates YAP activity in classic insulin target cells. We found by subcellular fractionation and Western blotting that insulin increases YAP phosphorylation, with a significant decrease in the abundance of YAP in the nuclei of HepG2 liver cells. Further, this regulation is likely mediated through the insulin receptor (IR), as overexpression of IR increased YAP phosphorylation. Proximity ligation assay analysis revealed a marked reduction in the interaction of YAP with TEA domain (TEAD) transcription factors in the nuclei of insulin-treated cells. Consistent with these findings, insulin significantly impaired YAP/TEAD-mediated transcription as measured by quantitative PCR in both HepG2 and C2C12 muscle cells. The inhibitory effect of insulin on YAP activity was abrogated by small-molecule inhibitors of phosphoinoinositide 3-kinase (PI3K). Insulin alters transcription of numerous genes relevant to energy homeostasis, and we observed that knockdown of YAP alters gexpression of genes in gluconeogenesis pathway. Collectively, our results identify insulin as a previously undescribed suppressor of YAP activity and provide insight into an important link between the insulin and Hippo pathways.
Scientific Focus Area: Molecular Biology and Biochemistry
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