Emerging mechanistic insights into mTOR‐PASK signaling pathway that connects nutrient signaling to chromatin network in stem cells

Abstract

Stem cell fate in the tissue niche is intimately connected with intracellular metabolic state and the extra‐cellular hormonal stimulations. We have shown that a sensory kinase, PAS domain Kinase (PASK) phosphorylates Wdr5, a member of COMPASS family of histone methyltransferases, to activate the stem cell differentiation program in multiple differentiation paradigms, in vivo and in vitro (eLife, 2016). PASK is expressed highly and exclusively in stem cells, yet the differentiation signaling cues are required to activate PASK and its downstream functions, suggesting PASK remains inaccessible to bind Wdr5 in proliferating stem cells. Here, we show that the mechanistic Target of Rapamycin (mTOR) phosphorylates PASK to promote Wdr5 recruitment and myogenesis in response to nutrient and hormonal signaling. How mTOR phosphorylation stimulates PASK‐Wdr5 interactions remains unknown but is a key mechanistic question that could help understand how nutrient and metabolic signaling can acutely control stem cell differentiation on demand. By using multi‐disciplinary approaches, we show that the PAS domain of PASK inhibits catalytic activity of the kinase domain. Interestingly, mTOR stimulated phosphorylation induces a conformational change resulting in the increased Wdr5 binding, and catalytic activity of PASK. Thus, our data show how information pertaining to nutrient availability is communicated to epigenetic complexes via sequential activation of the mTORC1‐PASK‐Wdr5 pathway.Support or Funding InformationNIH R01: Epigenetic Control of muscle stem cell function by PASK‐Wd5 signaling pathway.1R01AR073906‐01A1