Differential Effects of Myopathy-Associated Caveolin-3 Mutants on Growth Factor Signaling
| Autor: | Agnes Dreier, Eva Brauers, Berthold Wormland, Alexander Krüttgen, Andreas Roos, Joachim Weis |
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| Rok vydání: | 2010 |
| Předmět: |
Adult
Male medicine.medical_specialty Caveolin 3 medicine.medical_treatment Receptor Nerve Growth Factor Cell Line Pathology and Forensic Medicine Mice Muscular Diseases Epidermal growth factor Internal medicine Nerve Growth Factor Caveolin medicine Animals Humans Low-affinity nerve growth factor receptor Growth factor receptor inhibitor Epidermal growth factor receptor Extracellular Signal-Regulated MAP Kinases Epidermal Growth Factor biology Growth factor Middle Aged Rats Cell biology ErbB Receptors Endocrinology Nerve growth factor Mutation biology.protein Signal transduction Regular Articles Signal Transduction |
| Zdroj: | The American Journal of Pathology. 177:261-270 |
| ISSN: | 0002-9440 |
| DOI: | 10.2353/ajpath.2010.090741 |
| Popis: | Caveolin-3 is an important scaffold protein of cholesterol-rich caveolae. Mutations of caveolin-3 cause hereditary myopathies that comprise remarkably different pathologies. Growth factor signaling plays an important role in muscle physiology; it is influenced by caveolins and cholesterol-rich rafts and might thus be affected by caveolin-3 dysfunction. Prompted by the observation of a marked chronic peripheral neuropathy in a patient suffering from rippling muscle disease due to the R26Q caveolin-3 mutation and because TrkA is expressed by neuronal cells and skeletal muscle fibers, we performed a detailed comparative study on the effect of pathogenic caveolin-3 mutants on the signaling and trafficking of the TrkA nerve growth factor receptor and, for comparison, of the epidermal growth factor receptor. We found that the R26Q mutant slightly and the P28L strongly reduced nerve growth factor signaling in TrkA-transfected cells. Surface biotinylation experiments revealed that the R26Q caveolin-3 mutation markedly reduced the internalization of TrkA, whereas the P28L did not. Moreover, P28L expression led to increased, whereas R26Q expression decreased, epidermal growth factor signaling. Taken together, we found differential effects of the R26Q and P28L caveolin-3 mutants on growth factor signaling. Our findings are of clinical interest because they might help explain the remarkable differences in the degree of muscle lesions caused by caveolin-3 mutations and also the co-occurrence of peripheral neuropathy in the R26Q caveolinopathy case presented. |
| Databáze: | OpenAIRE |
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