Caveolin-3 in muscular dystrophy (original) (raw)
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Caveolin proteins in signaling, oncogenic transformation and muscular dystrophy
Journal of Cell Science, 2000
In adult animals and humans, signal transduction maintains homeostasis. When homeostatic mechanisms are interrupted, an illness or disease may ensue. Caveolae are plasma membrane specializations that contain the structural proteins caveolins, and appear to be important for normal signal transduction. The caveolin scaffolding domain interacts with several signaling molecules, sequestering them in the absence of activating signals, and thereby reducing the signal-to-noise ratio. Deletion and mutation of genes that encode caveolins is implicated in the pathogenesis of several human diseases. Down-regulation of caveolin-1 protein expression leads to deregulated signaling and consequently tumorigenesis, whereas naturally occurring dominant-negative caveolin-3 mutations cause muscular dystrophy.
AJP: Cell Physiology, 2003
Four different phenotypes have been associated with CAV3 mutations: limb girdle muscular dystrophy-1C (LGMD-1C), rippling muscle disease (RMD), and distal myopathy (DM), as well as idiopathic and familial hyperCKemia (HCK). Detailed molecular characterization of two caveolin-3 mutations (P104L and ΔTFT), associated with LGMD-1C, shows them to impart a dominant-negative effect on wild-type caveolin-3, rendering it dysfunctional through sequestration in the Golgi complex. Interestingly, substitution of glutamine for arginine at amino acid position 26 (R26Q) of caveolin-3 is associated not only with RMD but also with DM and HCK. However, the phenotypic behavior of the caveolin-3 R26Q mutation has never been evaluated in cultured cells. Thus we characterized the cellular and molecular properties of the R26Q mutant protein to better understand how this mutation can manifest as such distinct disease phenotypes. Here, we show that the caveolin-3 R26Q mutant is mostly retained at the level ...