Pask integrates hormonal signaling with histone modification via Wdr5 phosphorylation to drive myogenesis

Kikani, Chintan K.; Wu, Xiaoying; Paul, Litty; Sabic, Hana; Shen, Zuolian; Shakya, Arvind; Keefe, Alexandra C.; Villanueva, Claudio J.; Kardon, Gabrielle; Graves, Barbara J.; Tantin, Dean; Rutter, Jared

doi:10.7554/elife.17985

Cited by 17 publications

(67 citation statements)

References 73 publications

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“…Nutrients and Insulin Activate PASK in an mTORC1-Dependent Manner. We have previously reported that PASK expression was induced several-fold upon skeletal muscle injury and that loss of PASK resulted in severe defects in muscle regeneration (21). We showed that PASK activity was also posttranslationally stimulated during in vitro myogenesis (21).…”

Section: Resultsmentioning

confidence: 77%

“…We have previously reported that PASK expression was induced several-fold upon skeletal muscle injury and that loss of PASK resulted in severe defects in muscle regeneration (21). We showed that PASK activity was also posttranslationally stimulated during in vitro myogenesis (21). To understand if this activation of PASK is required for its prodifferentiation functions, we first asked if PASK is similarly activated during muscle regeneration in vivo.…”

Section: Resultsmentioning

confidence: 99%

“…*P < 0.05; ***P < 0.005. (21,22), was induced 3 d after injury. The increase in PASK activity coincided with the time point when both MyoG and endogenous mouse PASK expression is induced ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Our data show that PASK, via Wdr5 phosphorylation, collaborates with MyoD for transcriptional activation of Myog to drive the myogenesis program (21). Thus, we hypothesized that PASK and Wdr5 are intermediates of the signaling pathways that drive myogenesis (21). However, it remained unclear how differentiation signaling cues might activate the PASK-Wdr5 pathway.…”

mentioning

confidence: 92%

“…We have recently identified a signaling pathway downstream of the Per-Arnt-Sim domain kinase (PASK) protein kinase, which connects signaling cues to the phosphorylation of Wdr5, a member of MLL, SET1, and other histone-modifying enzymatic complexes, to drive transcriptional activation of Myog and myogenesis (21). Our data show that PASK, via Wdr5 phosphorylation, collaborates with MyoD for transcriptional activation of Myog to drive the myogenesis program (21). Thus, we hypothesized that PASK and Wdr5 are intermediates of the signaling pathways that drive myogenesis (21).…”

mentioning

confidence: 99%

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Activation of PASK by mTORC1 is required for the onset of the terminal differentiation program

Kikani

Fogarty

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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During skeletal muscle regeneration, muscle stem cells (MuSCs) respond to multiple signaling inputs that converge onto mammalian target of rapamycin complex 1 (mTORC1) signaling pathways. mTOR function is essential for establishment of the differentiationcommitted progenitors (early stage of differentiation, marked by the induction of myogenin expression), myotube fusion, and, ultimately, hypertrophy (later stage of differentiation). While a major mTORC1 substrate, p70S6K, is required for myotube fusion and hypertrophy, an mTORC1 effector for the induction of myogenin expression remains unclear. Here, we identified Per-Arnt-Sim domain kinase (PASK) as a downstream phosphorylation target of mTORC1 in MuSCs during differentiation. We have recently shown that the PASK phosphorylates Wdr5 to stimulate MuSC differentiation by epigenetically activating the myogenin promoter. We show that phosphorylation of PASK by mTORC1 is required for the activation of myogenin transcription, exit from self-renewal, and induction of the myogenesis program. Our studies reveal that mTORC1-PASK signaling is required for the rise of myogenin-positive committed myoblasts (early stage of myogenesis), whereas mTORC1-S6K signaling is required for myoblast fusion (later stage of myogenesis). Thus, our discoveries allow molecular dissection of mTOR functions during different stages of the myogenesis program driven by two different substrates. mTOR | PASK | myogenin | muscle stem cell | Pax7

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Section: Resultsmentioning

confidence: 77%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 92%

mentioning

confidence: 99%

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Activation of PASK by mTORC1 is required for the onset of the terminal differentiation program

Kikani

Fogarty

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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WDR5 positively regulates p53 stability by inhibiting p53 ubiquitination

Xie

Chen

2017

Biochemical and Biophysical Research Communications

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WD40 repeat protein WDR5 is a core component of the Set/MLL histone methyltransferase complex which catalyzes histone H3 Lys4 trimethylation and activates gene transcription in human cells. WDR5 promotes Set/MLL complex assembly and mediates the complex binding to Lys4-dimethylated histone H3 tail. Most earlier studies report that WDR5 exerts profound effects on various cellular and organismal processes mainly through epigenetic regulation of gene transcription. However, the functions of WDR5 in lung cancer remain largely unknown. Here, we report that WDR5 positively regulates p53 stability by inhibiting p53 ubiquitination in human lung cancer A549 cells. Overexpression of WDR5 dramatically increases p53 protein levels and its half-life in A549 cells, while depletion of WDR5 with WDR5-specific siRNAs significantly decreases p53 protein levels. We also observe that WDR5 is required for p53 induction in response to cisplatin treatment. Mechanistically, WDR5 colocalizes with p53 and inhibits p53 ubiquitination, resulting in p53 stabilization. Consequently, overexpression of WDR5 induces G1 phase arrest in A549 cells, and knocking down WDR5 by siRNAs reduces the population at G1 phase. Furthermore, p53 expression levels is at least in part determined by the p53 positive regulator WDR5 in some cancer cells. Taken together, these data suggest that WDR5 is directly involved in p53 signaling pathway. Our studies provide a new insight into WDR5 functions in A549 cells.

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MLL1 inhibits the neurogenic potential of SCAPs by interacting with WDR5 and repressing HES1

Zhang,

Ye,

Zhao

et al. 2023

Int J Oral Sci

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Mesenchymal stem cell (MSC)-based therapy has emerged as a promising treatment for spinal cord injury (SCI), but improving the neurogenic potential of MSCs remains a challenge. Mixed lineage leukemia 1 (MLL1), an H3K4me3 methyltransferases, plays a critical role in regulating lineage-specific gene expression and influences neurogenesis. In this study, we investigated the role and mechanism of MLL1 in the neurogenesis of stem cells from apical papilla (SCAPs). We examined the expression of neural markers, and the nerve repair and regeneration ability of SCAPs using dynamic changes in neuron-like cells, immunofluorescence staining, and a SCI model. We employed a coimmunoprecipitation (Co-IP) assay, real-time RT-PCR, microarray analysis, and chromatin immunoprecipitation (ChIP) assay to investigate the molecular mechanism. The results showed that MLL1 knock-down increased the expression of neural markers, including neurogenic differentiation factor (NeuroD), neural cell adhesion molecule (NCAM), tyrosine hydroxylase (TH), βIII-tubulin and Nestin, and promoted neuron-like cell formation in SCAPs. In vivo, a transplantation experiment showed that depletion of MLL 1 in SCAPs can restore motor function in a rat SCI model. MLL1 can combine with WD repeat domain 5 (WDR5) and WDR5 inhibit the expression of neural markers in SCAPs. MLL1 regulates Hairy and enhancer of split 1 (HES1) expression by directly binds to HES1 promoters via regulating H3K4me3 methylation by interacting with WDR5. Additionally, HES1 enhances the expression of neural markers in SCAPs. Our findings demonstrate that MLL1 inhibits the neurogenic potential of SCAPs by interacting with WDR5 and repressing HES1. These results provide a potential therapeutic target for promoting the recovery of motor function in SCI patients.

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Pask integrates hormonal signaling with histone modification via Wdr5 phosphorylation to drive myogenesis

Cited by 17 publications

References 73 publications

Activation of PASK by mTORC1 is required for the onset of the terminal differentiation program

Activation of PASK by mTORC1 is required for the onset of the terminal differentiation program

WDR5 positively regulates p53 stability by inhibiting p53 ubiquitination

MLL1 inhibits the neurogenic potential of SCAPs by interacting with WDR5 and repressing HES1

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