Rab5a activates IRS1 to coordinate IGF-AKT-mTOR signaling and myoblast differentiation during muscle regeneration
- 12 February 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Differentiation
- Vol. 27 (8), 2344-2362
- https://doi.org/10.1038/s41418-020-0508-1
Abstract
Rab5 is a master regulator for endosome biogenesis and transport while its in vivo physiological function remains elusive. Here, we find that Rab5a is upregulated in several in vivo and in vitro myogenesis models. By generating myogenic Rab5a-deficient mice, we uncover the essential roles of Rab5a in regulating skeletal muscle regeneration. We further reveal that Rab5a promotes myoblast differentiation and directly interacts with insulin receptor substrate 1 (IRS1), an essential scaffold protein for propagating IGF signaling. Rab5a interacts with IRS1 in a GTP-dependent manner and this interaction is enhanced upon IGF-1 activation and myogenic differentiation. We subsequently identify that the arginine 207 and 222 of IRS1 and tyrosine 82, 89, and 90 of Rab5a are the critical amino acid residues for mediating the association. Mechanistically, Rab5a modulates IRS1 activation by coordinating the association between IRS1 and the IGF receptor (IGFR) and regulating the intracellular membrane targeting of IRS1. Both myogenesis-induced and IGF-evoked AKT-mTOR signaling are dependent on Rab5a. Myogenic deletion of Rab5a also reduces the activation of AKT-mTOR signaling during skeletal muscle regeneration. Taken together, our study uncovers the physiological function of Rab5a in regulating muscle regeneration and delineates the novel role of Rab5a as a critical switch controlling AKT-mTOR signaling by activating IRS1.Funding Information
- China Postdoctoral Science Foundation (2019M662034)
- National Natural Science Foundation of China (31671479, 31671417)
This publication has 67 references indexed in Scilit:
- Regulation of TOR by small GTPasesEMBO Reports, 2012
- Rab5 GTPase controls chromosome alignment through Lamin disassembly and relocation of the NuMA-like protein Mud to the poles during mitosisProceedings of the National Academy of Sciences of the United States of America, 2011
- Small GTPase Rab5 participates in chromosome congression and regulates localization of the centromere-associated protein CENP-F to kinetochoresProceedings of the National Academy of Sciences of the United States of America, 2011
- Progenitors of skeletal muscle satellite cells express the muscle determination gene, MyoDDevelopmental Biology, 2009
- Rab GTPases as coordinators of vesicle trafficNature Reviews Molecular Cell Biology, 2009
- Endocytic Trafficking of Rac Is Required for the Spatial Restriction of Signaling in Cell MigrationCell, 2008
- Fast/Glycolytic Muscle Fiber Growth Reduces Fat Mass and Improves Metabolic Parameters in Obese MiceCell Metabolism, 2008
- Functional Interdependence at the Chromatin Level between the MKK6/p38 and IGF1/PI3K/AKT Pathways during Muscle DifferentiationMolecular Cell, 2007
- Critical nodes in signalling pathways: insights into insulin actionNature Reviews Molecular Cell Biology, 2006
- Duchenne muscular dystrophy and dystrophin: pathogenesis and opportunities for treatmentEMBO Reports, 2004