Unusual splicing events result in distinct Xin isoforms that associate differentially with filamin c and Mena/VASP

• Published in: Experimental cell research Vol. 312; no. 11; pp. 2154 - 2167
• Main Authors: van der Ven, Peter F.M., Ehler, Elisabeth, Vakeel, Padmanabhan, Eulitz, Stefan, Schenk, Jörg A., Milting, Hendrik, Micheel, Burkhard, Fürst, Dieter O.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2006; Elsevier BV
• Subjects: Actin cytoskeleton; Alternative Splicing; Animals; Animals, Newborn; Base Sequence; Binding Sites - genetics; Blotting, Western; Cell Adhesion Molecules - analysis; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Cells, Cultured; CMYA1; Contractile Proteins - analysis; Contractile Proteins - metabolism; Cytoskeletal Proteins - analysis; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Exons; Filamins; Gene expression; Genes; Genetic Variation; Humans; Intercalated disc; Intraexonic splicing; Microfilament Proteins - analysis; Microfilament Proteins - genetics; Microfilament Proteins - metabolism; Models, Biological; Molecular Sequence Data; Muscle development; Muscular system; Myocytes, Cardiac - chemistry; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Phosphoproteins - analysis; Phosphoproteins - genetics; Phosphoproteins - metabolism; Protein Isoforms - genetics; Protein Isoforms - metabolism; Protein Structure, Tertiary - genetics; Proteins; Rats; Xin repeat proteins; Xin repeat proteins; Muscle development; CMYA1; Actin cytoskeleton; Intercalated disc; Intraexonic splicing
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2006.03.015

Filamin c is the predominantly expressed filamin isoform in striated muscles. It is localized in myofibrillar Z-discs, where it binds FATZ and myotilin, and in myotendinous junctions and intercalated discs. Here, we identify Xin, the protein encoded by the human gene ‘cardiomyopathy associated 1’ ( CMYA1) as filamin c binding partner at these specialized structures where the ends of myofibrils are attached to the sarcolemma. Xin directly binds the EVH1 domain proteins Mena and VASP. In the adult heart, Xin and Mena/VASP colocalize with filamin c in intercalated discs. In cultured cardiomyocytes, the proteins also localize in the nonstriated part of myofibrils, where sarcomeres are assembled and an extensive reorganization of the actin cytoskeleton occurs. Unusual intraexonic splicing events result in the existence of three Xin isoforms that associate differentially with its ligands. The identification of the complex filamin c–Xin–Mena/VASP provides a first glance on the role of Xin in the molecular mechanisms involved in developmental and adaptive remodeling of the actin cytoskeleton during cardiac morphogenesis and sarcomere assembly.