Filamin 2 (FLN2): A Muscle-specific Sarcoglycan Interacting Protein

Abstract

Mutations in genes encoding for the sarcoglycans, a subset of proteins within the dystrophin–glycoprotein complex, produce a limb-girdle muscular dystrophy phenotype; however, the precise role of this group of proteins in the skeletal muscle is not known. To understand the role of the sarcoglycan complex, we looked for sarcoglycan interacting proteins with the hope of finding novel members of the dystrophin–glycoprotein complex. Using the yeast two-hybrid method, we have identified a skeletal muscle-specific form of filamin, which we term filamin 2 (FLN2), as a γ- and δ-sarcoglycan interacting protein. In addition, we demonstrate that FLN2 protein localization in limb-girdle muscular dystrophy and Duchenne muscular dystrophy patients and mice is altered when compared with unaffected individuals. Previous studies of filamin family members have determined that these proteins are involved in actin reorganization and signal transduction cascades associated with cell migration, adhesion, differentiation, force transduction, and survival. Specifically, filamin proteins have been found essential in maintaining membrane integrity during force application. The finding that FLN2 interacts with the sarcoglycans introduces new implications for the pathogenesis of muscular dystrophy.

The genetic and molecular basis of muscular dystrophy: roles of cell–matrix linkage in the pathogenesis

“…A primary mutation in any one of the SG genes leads to concomitant reduction of the entire SG complex. The exact function of the SGsarcospan complex is still unknown, but some putative functions have been proposed; it may stabilize the DGC components in the muscle membrane Straub et al 1998); it may regulate localization of c-filamin (Thompson et al 2000). Using animal models and virus-gene transfer techniques, it has been demonstrated that genetic deficiencies of the SG complex can be corrected in vivo Durbeej et al 2003).…”

Cytoplasmic γ-actin expression in diverse animal models of muscular dystrophy

“…The actin binding proteins γ-filamin, talin, vinculin, plectin and utrophin are all upregulated and/or redistributed to costameres in dystrophin-deficient muscle [4,5,[32][33][34]. With the exception of utrophin, all of these proteins interact with integrins in vivo and α7β1 integrin is also upregulated in dystrophin-deficient muscle [35,36].…”

Telethonin and Other New Proteins of the Z‐Disc of Skeletal Muscle

“…Interestingly,°-lamin is the only isoform with a unique 78-amino acid insertion in the Ig-like domain 20, and this insertion has been shown to be responsible for targeting°-lamin to Z-disc of striated muscle (39). The N-terminal of°-lamin is located at the periphery of the Z-disc (37,38 ) and recently this region has been found to bind to myotilin, an ®-actinin-binding protein (39 ). During a search for proteins binding to sarcoglycans,°-lamin was found to bind speci cally to°-and ±-but not ®-and¯-sarcoglycans (38).…”

“…The N-terminal of°-lamin is located at the periphery of the Z-disc (37,38 ) and recently this region has been found to bind to myotilin, an ®-actinin-binding protein (39 ). During a search for proteins binding to sarcoglycans,°-lamin was found to bind speci cally to°-and ±-but not ®-and¯-sarcoglycans (38). In normal muscle°-lamin is found mainly in the Z-disc but also at low levels in the sarcolemma, whereas in muscle with mutations in°-sarcoglycan, ±-sarcoglycan, or dystrophin, there is an increase in the°-lamin level in the sarcolemma.…”

“…There are three isoforms, lamin (ABP-280) that is ubiquitous,°-lamin (ABP-L, lamin2) that is speci c for striated muscle (37,38 ), and¯-lamin. All of these isoforms have an N-terminal actinbinding domain followed by 24 Ig-like repeats and a C-terminal domain necessary for dimer formation.…”