Limb girdle muscular dystrophy 2C is caused by mutations in the gamma-sarcoglycan gene (gsg) that results in loss of this protein, and disruption of the sarcoglycan (SG) complex. Signal transduction after mechanical perturbation is mediated, in part, through the SG complex and leads to phosphorylation of tyrosines on the intracellular portions of the sarcoglycans. This study tested if the Tyr(6) in the intracellular region of gamma-sarcoglycan protein (gamma-SG) was necessary for proper localization of the protein in skeletal muscle membranes or for the normal pattern of ERK1/2 phosphorylation after eccentric contractions. Viral mediated gene transfer of wild type gsg (WTgsg) and mutant gsg lacking Tyr(6) (Y6Agsg) was performed into the muscles of gsg(-/-) mice. Muscles were examined for production and stability of the gamma-SG, as well as the level of ERK1/2 phosphorylation before and after eccentric contraction. Sarcolemmal localization of gamma-SG was achieved regardless of which construct was expressed. However, only expression of WTgsg corrected the aberrant ERK1/2 phosphorylation associated with the absence of gamma-SG, whereas Y6Agsg failed to have any effect. This study shows that localization of gamma-SG does not require Tyr(6), but localization alone is insufficient for restoration of normal signal transduction patterns after mechanical perturbation.