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¹ Netherlands Cancer Institute, Division of Cell Biology, 1066 CX Amsterdams, Netherlands
² Cardeza Foundation for Hematologic Research, Department of Medicine, Jefferson Medical College, Philadelphia, PA 19107

Address correspondence to Arnoud Sonnenberg, Division of Cell Biology, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands. Tel.: (31) 20-512-1942. Fax: (31) 20-512-1944. E-mail: asonn{at}nki.nl

Integrins connect the extracellular matrix with the cell interior, and transduce signals through interactions of their cytoplasmic tails with cytoskeletal and signaling proteins. Using the yeast two-hybrid system, we isolated a novel splice variant (filamin-B_var-1) of the filamentous actin cross-linking protein, filamin-B, that interacts with the cytoplasmic domain of the integrin ß1A and ß1D subunits. RT-PCR analysis showed weak, but wide, expression of filamin-B_var-1 and a similar splice variant of filamin-A (filamin-A_var-1) in human tissues. Furthermore, alternative splice variants of filamin-B and filamin-C, from which the flexible hinge-1 region is deleted (H1), were induced during in vitro differentiation of C2C12 mouse myoblasts. We show that both filamin-A_var-1 and filamin-B_var-1 bind more strongly than their wild-type isoforms to different integrin ß subunits. The mere presence of the high-affinity binding site for ß1A is not sufficient for targeting the filamin-B_var-1 construct to focal contacts. Interestingly, the simultaneous deletion of the H1 region is required for the localization of filamin-B at the tips of actin stress fibers. When expressed in C2C12 cells, filamin-B_var-1(H1) accelerates their differentiation into myotubes. Furthermore, filamin-B variants lacking the H1 region induce the formation of thinner myotubes than those in cells containing variants with this region. These findings suggest that specific combinations of filamin mRNA splicing events modulate the organization of the actin cytoskeleton and the binding affinity for integrins.

Key Words: filamin isoforms; alternative splicing; ß1D integrin; myogenesis; cytoskeleton

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