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Vol. 18, Issue 12, 4731-4740, December 2007

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Identification of CAP as a Costameric Protein that Interacts with Filamin C

Departments of Internal Medicine and Physiology, Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109

Submitted July 2, 2007; Revised September 13, 2007; Accepted September 14, 2007
Monitoring Editor: Yu-li Wang

Cbl-associated protein (CAP) is an adaptor protein that interacts with both signaling and cytoskeletal proteins. Here, we characterize the expression, localization and potential function of CAP in striated muscle. CAP is markedly induced during myoblast differentiation, and colocalizes with vinculin during costamerogenesis. In adult mice, CAP is enriched in oxidative muscle fibers, and it is found in membrane anchorage complexes, including intercalated discs, costameres, and myotendinous junctions. Using both yeast two-hybrid and proteomic approaches, we identified the sarcomeric protein filamin C (FLNc) as a binding partner for CAP. When overexpressed, CAP recruits FLNc to cell–extracellular matrix adhesions, where the two proteins cooperatively regulate actin reorganization. Moreover, overexpression of CAP inhibits FLNc-induced cell spreading on fibronectin. In dystrophin-deficient mdx mice, the expression and membrane localization of CAP is increased, concomitant with the elevated plasma membrane content of FLNc, suggesting that CAP may compensate for the reduced membrane linkage of the myofibrils due to the loss of the dystroglycan–sarcoglycan complex in these mice. Thus, through its interaction with FLNc, CAP provides another link between the myofibril cytoskeleton and the plasma membrane of muscle cells, and it may play a dynamic role in the regulation and maintenance of muscle structural integrity.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

* Present address: Kentucky Pediatric Research Institute, University of Kentucky School of Medicine, Lexington, KY 40536.

Address correspondence to: Alan R. Saltiel (saltiel{at}lsi.umich.edu).

Abbreviations used: CAP, cbl-associated protein; DGC, dystrophin-glycoprotein complex; ECM, extracellular matrix; FLNc, filamin C.