Differential Effects of Myopathy-Associated Caveolin-3 Mutants on Growth Factor Signaling

Abstract

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.

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

“…As for caveolin-1, caveolin-3 expression appears to suppress EGFR signalling (Brauers et al, 2010), consistent with early reports of EGFR inhibition by caveolin-3 (Couet et al, 1997). Dissociation from caveolin-3 upon receptor activation, as observed for ErbB4 (Zhao et al, 1999), could be important in initiating EGFR signalling (caveolin-3 suppressing basal activity, dissociation facilitating signalling activation).…”

Lack of functional caveolae in Cav3 mutated human dystrophic myotubes results in deficient mechanoprotection and IL6/STAT3 mechanosignaling

“…1c). On the contrary, in the P28L and R26Q myotubes, Cav3 showed a drastic accumulation in the Golgi complex, as shown by the strong colocalization with GM130, in agreement with published data Brauers et al, 2010). These data confirm that the Cav3 P28L and R26Q mutations retain Cav3 in the Golgi complex, which results in a drastic reduction of the number of caveolae present at the plasma membrane of the Cav3 mutant myotubes.…”

“…Furthermore, Cav3 is involved in the regulation of different signaling pathways important for muscle function such as calcium homeostasis (Weiss et al, 2008), the insulin/GLUT4/Akt pathway (Fecchi et al, 2006) or TrkA and EGFR signaling (Brauers et al, 2010). Finally, we showed a role of Cav3 in membrane tension buffering and mechanoprotection in P28L FHCK human myotubes (Sinha et al, 2011).…”

“…These two heterozygous mutations both lead to the abnormal retention of Cav3 in the Golgi complex. The P28L and R26Q Cav3 mutations have so far been associated to deregulations of some signaling pathways Brauers et al, 2010), defects in membrane repair (Hernandez-Deviez et al, 2008;Cai et al, 2009) and defect in the mechanoprotection of the muscle tissue (Lo et al, 2015).…”

CAV3gene sequence variations: National Genome Database and clinics

“…It is a highly evolutionarily conserved gene, suggesting a vital function; therefore, frequent sequence variations at this locus are not expected . CAV3 mutations mainly disturb normal cell signaling pathways, change muscle cell structural integrity, and lead to apoptosis . Most caveolinopathies are transmitted with an autosomal dominant inheritance .…”