Skeletal muscle signaling pathway through the dystrophin glycoprotein complex and Rac1.
The dystrophin glycoprotein complex has been proposed to be involved in signal transduction. Here we have shown that laminin binding causes syntrophin to recruit Rac1 from the rabbit skeletal muscle. Laminin-Sepharose and syntrophin-Sepharose bind a protein complex containing Rac1 from the muscle membranes. The presence of heparin, which inhibits laminin interactions, prevents recruitment of Rac1. The dystrophin glycoprotein complex recruits Rac1 via syntrophin through a Grb2.Sos1 complex. A syntrophin antibody also prevents recruitment of Rac1, suggesting that the signaling complex requires syntrophin. PAK1 is in turn bound by Rac1. c-Jun NH2-terminal kinase-p46 is phosphorylated and activated only when laminin is present, and the p54 isoform is activated when laminin is depleted or binding is inhibited with heparin. In the presence of laminin, c-Jun is activated in both skeletal muscle microsomes and in C2C12 myoblasts, and proliferation increases in C2C12 myoblasts. We postulate that this pathway signals muscle homeostasis and hypertrophy.
Oak
Shilpa A
SA
Department of Biochemistry, University of Tennessee, Memphis, Tennessee 38163, USA.
Zhou
Yan Wen
YW
Jarrett
Harry W
HW
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002460:Cell Line; D016189:Dystrophin / Q000737:chemistry / Q000378:metabolism*; D049029:Dystrophin-Associated Proteins; D004789:Enzyme Activation; D051380:GRB2 Adaptor Protein; D006023:Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases; D007797:Laminin / Q000378:metabolism; D046911:Macromolecular Substances; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D032448:Myoblasts, Skeletal / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D016189:Dystrophin; D049029:Dystrophin-Associated Proteins; D051380:GRB2 Adaptor Protein; D006023:Glycoproteins; C495949:Grb2 protein, mouse; D007797:Laminin; D046911:Macromolecular Substances; D008565:Membrane Proteins; D009124:Muscle Proteins; D011506:Proteins; D011993:Recombinant Fusion Proteins; C091824:syntrophin; C515905:Pak1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein