TC10 controls human myofibril organization and is activated by the sarcomeric RhoGEF obscurin.
The contractile activity of striated muscle depends on myofibrils that are highly ordered macromolecular complexes. The protein components of myofibrils are well characterized, but it remains largely unclear how signaling at the molecular level within the sarcomere and the control of assembly are coordinated. We show that the Rho GTPase TC10 appears during differentiation of human primary skeletal myoblasts and it is active in differentiated myotubes. We identify obscurin, a sarcomere-associated protein, as a specific activator of TC10. Indeed, TC10 binds directly to obscurin via its predicted RhoGEF motif. Importantly, we demonstrate that obscurin is a specific activator of TC10 but not the Rho GTPases Rac and Cdc42. Finally, we show that inhibition of TC10 activity by expression of a dominant-negative mutant or its knockdown by expression of specific shRNA block myofibril assembly. Our findings reveal a novel signaling pathway in human skeletal muscle that involves obscurin and the Rho GTPase TC10 and implicate this pathway in new sarcomere formation.
Coisy-Quivy
Marjorie
M
INSERM, ERI 25, Muscle and Pathologies, F-34295 Montpellier, France.
Touzet
Olivia
O
Bourret
Annick
A
Hipskind
Robert A
RA
Mercier
Jacques
J
Fort
Philippe
P
Philips
Alexandre
A
D002454:Cell Differentiation; D002478:Cells, Cultured; D004789:Enzyme Activation; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000201:enzymology; D009124:Muscle Proteins / Q000737:chemistry / Q000378:metabolism*; D009210:Myofibrils / Q000201:enzymology*; D038081:Organogenesis; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors; D012518:Sarcomeres / Q000201:enzymology / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
D020662:Guanine Nucleotide Exchange Factors; D009124:Muscle Proteins; D034741:RNA, Small Interfering; D064067:Rho Guanine Nucleotide Exchange Factors; C578224:OBSCN protein, human; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; C503256:RHOQ protein, human; D020741:rho GTP-Binding Proteins