Transcriptional control of PPP2CB by YAP1 and TEAD1 mediates AMPK inhibition and mTORC1 activation in vascular smooth muscle cells

We previously demonstrated that the transcriptional co-factor Yes-associated protein 1 (YAP1) promotes vascular smooth muscle cell (VSMC) phenotypic switching and neointima formation. However, the underlying mechanisms remain unclear. Here, using YAP1 silencing and overexpression assays in human VSMCs, we demonstrate that YAP1 is necessary and sufficient to activate mammalian target of rapamycin complex 1 (mTORC1) and that mTORC1 activity is required for YAP1-induced VSMC proliferation. Mechanistically, we report that YAP1 inhibits AMP-activated protein kinase (AMPK), a negative regulator of mTORC1, thereby relieving AMPK-mediated suppression of mTORC1. We identify the protein phosphatase 2A catalytic subunit PPP2CB as a YAP1-regulated transcriptional target that contributes to AMPK inhibition and mTORC1 activation. We further show that a transcription factor, transcriptional enhancer activator domain 1 (TEAD1), mediates YAP1-dependent PPP2CB expression and that the upstream AMPK kinase CAMKK2 is required for YAP1-dependent modulation of AMPK/mTORC1 signaling. Together, these results define a YAP1/AMPK/mTORC1 signaling axis that drives VSMC proliferation, with potential broader relevance given the ubiquitous expression of these signaling molecules.