Muscle Cell Signaling

肌肉细胞信号传导

• 批准号: 7372006
• 负责人: HARRY W JARRETT
• 金额: $ 23.7万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7372006
• 关键词: Accounting; Actins; Affect; Anoikis; Apoptosis; Atrophic; Binding; Binding Sites; Blocking Antibodies; Body Regions; Cell Death; Cell Proliferation; Cell Survival; Cell-Matrix Junction; Cells; Cessation of life; Complex; Contracts; Cytoskeleton; Defect; Dose; Duchenne muscular dystrophy; Dystroglycan; Dystrophin; Environment; Event; Extracellular Matrix; Fiber; Functional disorder; Genes; Genetic; Glycoproteins; Heterotrimeric GTP-Binding Proteins; Homeostasis; Hypertrophy; Integrin Binding; Integrins; Investigation; JUN gene; Laboratories; Laminin; Lesion; Life; Link; Localized; Location; MAPK14 gene; MAPK8 gene; Measures; Mechanics; Mechanoreceptors; Merosin; Modeling; Motion; Muscle; Muscle Cells; Muscle Fibers; Muscular Atrophy; Muscular Dystrophies; Mutation; Myoblasts; Myopathy; Nature; PTK2 gene; Pathway interactions; Phosphorylation; Physiological; Prevention; Process; Property; Protein Isoforms; Protein Kinase; Protein Tyrosine Kinase; Proteins; Proto-Oncogene Proteins c-akt; Range; Receptor Signaling; Research Personnel; Role; SRC gene; Sarcolemma; Signal Pathway; Signal Transduction; Site; Skeletal Muscle; Stretching; Sum; Suspension substance; Suspensions; Testing; cell growth; congenital muscular dystrophy; inhibitor/antagonist; prevent; receptor; research study; response; satellite cell; src-Family Kinases; syntrophin

Many muscular dystrophies are caused by defects in the dystrophin glycoprotein complex (DGC). The DGC and integrins bind extracellular matrix laminin-2 (o2BlYl) and defects in laminin-2 or a7(31 integrin cause other myopathies. Laminin-binding to either the DGC or integrins causes changes in the cell's signaling pathways, can effect cell survival and proliferation, and is germane to the myopathies and to muscle atrophy. Cell signaling arising at laminin/DGC/integrin is already known to be quite complex. We will characterize the protein tyrosine kinase which may be one of the earliest events in this signaling and localize the site of syntrophin phosphorylation. The physiological function of this signaling is not known but may be related to mechanoreception or anoikis. When muscle is contracted or stretched, fiber strength is maintain- ed, but when unstimulated it atrophies. The laminin/DGC/integrin signaling may be a normal physiological response to this mechanical motion, maintaining the muscle. Anoikis is the process by which cells not lo- cated in a normal cellular environment undergo apoptosis. We will test these two alternative hypotheses by determining the effect of laminin/cell attachment and stretching/contraction on the cell signaling originating at the DGC and integrins and determine if apoptosis or proliferative signaling is affected. Using inhibitors and blocking antibodies, we will determine whether the DGC or a7(31 integrin is involved in the affected signaling. Other signaling pathwaysthrough p38, ERK1/2, AKT, JNK, FAK, Gs, and c-src family kinases have all been linked to the binding of extracellular matrix to the sarcolemma. The activation and location of each of these will be determined as myocytes bind extracellular matrix components and as the myocytes are stretch, held in suspension, or allowed to attachto matrix. The extent of apoptosis will also be determined and the sum of these will give a clear picture of how viability is affected by these signaling events. The five globular domains of laminin's a-subunit (LG1-5) provide binding sites for integrins and the DGC. We have expressed and purified the laminin a1-LG4-5 domain and have shown that, depending on dose, it can cause cell proliferation or death. Another collaborator has provided the Q2-LG4-5domain protein. By comparing the effects of the two proteins on cell viability and cell signaling, we will determine the receptor responsible for proliferative and death responses and the nature of the cell death observed. By truncation mutation, we will further localize the laminin-a sequences responsible.

许多肌营养不良症是由肌营养不良蛋白糖蛋白复合物（DGC）缺陷引起的。的