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PASsing on signals: Activation of PAS kinase by mTOR orchestrates epigenetic processes of stem cell differentiation
Author(s) -
Kikani Chintan K,
Wu Xiaoying,
Rutter Jared
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.614.28
Subject(s) - myogenesis , pi3k/akt/mtor pathway , mtorc1 , myogenin , microbiology and biotechnology , biology , h3k4me3 , phosphorylation , kinase , signal transduction , biochemistry , myocyte , gene expression , promoter , gene
Per‐ARNT‐Sim (PAS) domains are versatile sensors of intra‐ and extra‐cellular metabolic environment. We have recently shown that in response to various pro‐differentiation signaling cues, PAS domain containing protein Kinase (PAS Kinase, or PASK), regulates the differentiation of stem cells via phosphorylation of Wdr5. Wdr5 is a member of histone trimethylation at Lysine 4 (H3K4me3) enzymatic complexes. Wdr5 phosphorylation by PASK regulates H3K4me3 modification at the Myogenin promoter resulting in its activation during myogenesis. However, it remained unclear how PASK function is regulated in stem cells by differentiation signaling cues. Here we show that PASK is activated by nutrients such as glucose and amino acids and hormones such as insulin and IGF‐1 in muscle stem cells. This activation of PASK is mediated by mTOR Complex 1 (mTORC1). PASK forms a nutrient‐sensitive complex with mTORC1, and in response to nutrient signaling, mTOR directly phosphorylates PASK on multiple residues. This activation of PASK by mTOR recruits Wdr5 onto PASK, resulting in an increased Wdr5 phosphorylation. Finally, during myogenesis, both PASK and mTOR regulates the induction of the Myogenin mRNA expression and myogenesis program via Wdr5 phosphorylation. Since muscle is a metabolically active tissue, our findings suggest that metabolic cues such as glucose and amino‐acids and insulin co‐ordinates cellular metabolism with myogenesis program via mTOR‐PASK signaling.Epigenetic control of Myogenesis program via mTOR‐PASK‐Wdr5 signaling. Metabolic cues such as insulin and nutrients activates PASK via mTOR mediated phosphorylation. Activated PASK phosphorylates Wdr5 to promote H3K4me3 modification on Myogenin promoter resulting in its activation. Myogenin regulates PASK expression in positive feedback manner to reinforce the differentiation program.