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A caveolin-3 mutant that causes limb girdle muscular dystrophy type 1C disrupts Src localization and activity and
Gayle M Smythe1, Joshua C Eby, Marie-Helene Disatnik
1Department of Neurology and Neurological Science, Stanford University School of Medicine, Stanford, California 94305-5235, USA.
Abstract:
Caveolins are membrane proteins that are the major coat proteins of caveolae, specialized lipid rafts in the plasma membrane that serve as scaffolding sites for many signaling complexes. Among the many signaling molecules associated with caveolins are the Src tyrosine kinases, whose activation regulates numerous cellular functions including the balance between cell survival and cell death. Several mutations in the muscle-specific caveolin, caveolin-3, lead to a form of autosomal dominant muscular dystrophy referred to as limb girdle muscular dystrophy type 1C (LGMD-1C). One of these mutations (here termed the 'TFT mutation') results in a deletion of a tripeptide (DeltaTFT(63-65)) that affects the scaffolding and oligomerization domains of caveolin-3. This mutation causes a 90-95% loss of caveolin-3 protein levels and reduced formation of caveolae in skeletal muscle fibers. However, the effects of this mutation on the specific biochemical processes and cellular functions associated with caveolae have not been elucidated. We demonstrate that the TFT caveolin-3 mutation in post-mitotic skeletal myotubes causes severely reduced localization of caveolin-3 to the plasma membrane and to lipid rafts, and significantly inhibits caveolar function. The TFT mutation reduced the binding of Src to caveolin-3, diminished targeting of Src to lipid rafts, and caused abnormal perinuclear accumulation of Src. Along with these alterations of Src localization and targeting, there was elevated Src activation in myotubes expressing the TFT mutation and an increased incidence of apoptosis in those cells compared with control myotubes. The results of this study demonstrate that caveolin-3 mutations associated with LGMD-1C disrupt normal cellular signal transduction pathways associated with caveolae and cause apoptosis in muscle cells, all of which may reflect pathogenetic pathways that lead to muscle degeneration in these disorders.
Insights
A caveolin-3 mutation linked to limb girdle muscular dystrophy type 1C disrupts Src signaling and caveolae function, leading to muscle cell apoptosis and potential muscle degeneration.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Caveolins are essential membrane proteins forming caveolae, which scaffold signaling complexes.
- Caveolin-3 is crucial in skeletal muscle; mutations cause limb girdle muscular dystrophy type 1C (LGMD-1C).
- The TFT mutation in caveolin-3 leads to protein loss and reduced caveolae formation.
Purpose of the Study:
- To investigate the functional consequences of the TFT caveolin-3 mutation on cellular signaling and caveolae function.
- To elucidate the impact of this mutation on Src tyrosine kinase localization and activation.
- To determine if the TFT mutation contributes to muscle cell apoptosis.
Main Methods:
- Studied post-mitotic skeletal myotubes expressing the TFT caveolin-3 mutation.
- Assessed caveolin-3 localization to the plasma membrane and lipid rafts.
- Analyzed Src binding to caveolin-3, Src targeting to lipid rafts, and Src activation.
- Quantified apoptosis incidence in myotubes.
Main Results:
- The TFT mutation severely impaired caveolin-3 localization and caveolar function.
- Src binding to caveolin-3 was reduced, and Src targeting to lipid rafts was diminished.
- Abnormal Src accumulation occurred near the nucleus, alongside elevated Src activation and increased apoptosis.
Conclusions:
- LGMD-1C-associated caveolin-3 mutations disrupt caveolae-mediated signaling pathways.
- Altered Src signaling and increased apoptosis in muscle cells may underlie muscle degeneration in LGMD-1C.
- The TFT mutation provides a model for understanding disease pathogenesis.
