TC10 controls human myofibril organization and is activated by the sarcomeric RhoGEF obscurin

Coisy-Quivy, Marjorie; Touzet, Olivia; Bourret, Annick; Hipskind, Robert A.; Mercier, Jacques; Fort, Philippe; Philips, Alexandre

doi:10.1242/jcs.040121

Cited by 22 publications

(29 citation statements)

References 43 publications

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“…Recent studies have identified RhoA (Ford et al, 2008) and TC10, also known as RhoQ (Coisy-Quivy et al, 2009), as targets for activation by the obscurin RhoGEF domain. Demonstration that the RhoGEF domain of Unc-89, the invertebrate orthologue of obscurin, is capable of activating Rho1, the invertebrate orthologue of RhoA (Qadota et al, 2008) further supports RhoA as a target of obscurin-mediated signaling.…”

Section: Discussionmentioning

confidence: 99%

Targeted deletion of the zebrafish obscurin A RhoGEF domain affects heart, skeletal muscle and brain development

Raeker

Bieniek

Ryan

et al. 2010

Developmental Biology

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Obscurin is a giant structural and signaling protein that participates in the assembly and structural integrity of striated myofibrils. Previous work has examined the physical interactions between obscurin and other cytoskeletal elements but its in vivo role in cell signaling, including the functions of its RhoGTPase Exchange Factor (RhoGEF) domain have not been characterized. In this study, morpholino antisense oligonucleotides were used to create an in-frame deletion of the active site of the obscurin A RhoGEF domain in order to examine its functions in zebrafish development. Cardiac myocytes in the morphant embryos lacked the intercalated disks that were present in controls by 72 hpf and, in the more severely affected embryos, the contractile filaments were not organized into mature sarcomeres. Neural abnormalities included delay or loss of retinal lamination. Rescue of the phenotype with co-injection of mini-obscurin A expression constructs demonstrated that the observed effects were due to the loss of small GTPase activation by obscurin A. The immature phenotype of the cardiac myocytes and the retinal neuroblasts observed in the morphant embryos suggests that obscurin A-mediated small GTPase signaling promotes tissue-specific cellular differentiation. This is the first demonstration of the importance of the obscurin A-mediated RhoGEF signaling in vertebrate organogenesis and highlights the central role of obscurin A in striated muscle and neural development.

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Section: Discussionmentioning

confidence: 99%

Targeted deletion of the zebrafish obscurin A RhoGEF domain affects heart, skeletal muscle and brain development

Raeker

Bieniek

Ryan

et al. 2010

Developmental Biology

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“…In addition to binding and activating RhoA, the obscurin RhoGEF motif interacts with and activates TC10 that also belongs to the Rho family of GTPases (104). TC10 appears after the fusion of myoblasts, and its expression is maintained in differentiating and mature myotubes (103).…”

Section: Obscurinmentioning

confidence: 99%

“…TC10 appears after the fusion of myoblasts, and its expression is maintained in differentiating and mature myotubes (103). Downregulation or overexpression of a dominant-negative form of TC10 in human myotubes demonstrated that it is essential for myofibril assembly, indicating that the interaction of obscurin RhoGEF and TC10 may play key roles in sarcomerogenesis (104). …”

Section: Obscurinmentioning

confidence: 99%

Thick Filament Protein Network, Functions, and Disease Association

Wang

Geist

Grogan

et al. 2018

Comprehensive Physiology

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Sarcomeres consist of highly ordered arrays of thick myosin and thin actin filaments along with accessory proteins. Thick filaments occupy the center of sarcomeres where they partially overlap with thin filaments. The sliding of thick filaments past thin filaments is a highly regulated process that occurs in an ATP-dependent manner driving muscle contraction. In addition to myosin that makes up the backbone of the thick filament, four other proteins which are intimately bound to the thick filament, myosin binding protein-C, titin, myomesin, and obscurin play important structural and regulatory roles. Consistent with this, mutations in the respective genes have been associated with idiopathic and congenital forms of skeletal and cardiac myopathies. In this review, we aim to summarize our current knowledge on the molecular structure, subcellular localization, interacting partners, function, modulation via posttranslational modifications, and disease involvement of these five major proteins that comprise the thick filament of striated muscle cells. © 2018 American Physiological Society. Compr Physiol 8:631-709, 2018.

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“…TC10, a small GTPase not previously thought to influence the biology of striated muscle, is expressed in skeletal myotubes and is activated by obscurin's Rho-GEF domain. This is likely to play a role in later stages of differentiation, as inhibition of TC10 activity blocks myofibrillogenesis (53). The ability of obscurin to activate small GTPases in muscle, and the factors that influence this activation, are likely to play a wide range of important roles in the plasticity of muscle tissue, in particular during development, as well as in its response to injury or during atrophy or hypertrophy.…”

Section: Obscurinmentioning

confidence: 99%

Muscle Giants: Molecular Scaffolds in Sarcomerogenesis

Kontrogianni‐Konstantopoulos

Ackermann

Bowman³

et al. 2009

Physiological Reviews

222

259

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Myofibrillogenesis in striated muscles is a highly complex process that depends on the coordinated assembly and integration of a large number of contractile, cytoskeletal, and signaling proteins into regular arrays, the sarcomeres. It is also associated with the stereotypical assembly of the sarcoplasmic reticulum and the transverse tubules around each sarcomere. Three giant, muscle-specific proteins, titin (3–4 MDa), nebulin (600–800 kDa), and obscurin (~720–900 kDa), have been proposed to play important roles in the assembly and stabilization of sarcomeres. There is a large amount of data showing that each of these molecules interacts with several to many different protein ligands, regulating their activity and localizing them to particular sites within or surrounding sarcomeres. Consistent with this, mutations in each of these proteins have been linked to skeletal and cardiac myopathies or to muscular dystrophies. The evidence that any of them plays a role as a “molecular template,” “molecular blueprint,” or “molecular ruler” is less definitive, however. Here we review the structure and function of titin, nebulin, and obscurin, with the literature supporting a role for them as scaffolding molecules and the contradictory evidence regarding their roles as molecular guides in sarcomerogenesis.

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TC10 controls human myofibril organization and is activated by the sarcomeric RhoGEF obscurin

Cited by 22 publications

References 43 publications

Targeted deletion of the zebrafish obscurin A RhoGEF domain affects heart, skeletal muscle and brain development

Targeted deletion of the zebrafish obscurin A RhoGEF domain affects heart, skeletal muscle and brain development

Thick Filament Protein Network, Functions, and Disease Association

Muscle Giants: Molecular Scaffolds in Sarcomerogenesis

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