Functional Interdependence at the Chromatin Level between the MKK6/p38 and IGF1/PI3K/AKT Pathways during Muscle Differentiation

Carlo Serra, Daniela Palacios, Chiara Mozzetta, Sonia V. Forcales, Ianessa Morantte, Meri Ripani, David R. Jones, Keyong Du, Ulupi S. Jhala, Cristiano Simone, Pier Lorenzo Puri

Research output: Contribution to journalArticlepeer-review

Abstract

During muscle regeneration, the mechanism integrating environmental cues at the chromatin of muscle progenitors is unknown. We show that inflammation-activated MKK6-p38 and insulin growth factor 1 (IGF1)-induced PI3K/AKT pathways converge on the chromatin of muscle genes to target distinct components of the muscle transcriptosome. p38 α/β kinases recruit the SWI/SNF chromatin-remodeling complex; AKT1 and 2 promote the association of MyoD with p300 and PCAF acetyltransferases, via direct phosphorylation of p300. Pharmacological or genetic interference with either pathway led to partial assembly of discrete chromatin-bound complexes, which reflected two reversible and distinct cellular phenotypes. Remarkably, PI3K/AKT blockade was permissive for chromatin recruitment of MEF2-SWI/SNF complex, whose remodeling activity was compromised in the absence of MyoD and acetyltransferases. The functional interdependence between p38 and IGF1/PI3K/AKT pathways was further established by the evidence that blockade of AKT chromatin targets was sufficient to prevent the activation of the myogenic program triggered by deliberate activation of p38 signaling.

Original languageEnglish
Pages (from-to)200-213
Number of pages14
JournalMolecular Cell
Volume28
Issue number2
DOIs
Publication statusPublished - Oct 26 2007

Keywords

  • DNA
  • SIGNALING

ASJC Scopus subject areas

  • Molecular Biology

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