The syntrophin family of dystrophin-associated proteins consists of three isoforms, ␣1, ␤1, and ␤2, each encoded by a distinct gene. We have cloned and characterized the mouse ␣1-and ␤2-syntrophin genes. The mouse ␣1-syntrophin gene (>24 kilobases) is comprised of eight exons. The mouse ␤2-syntrophin gene (>33 kilobases) contains seven exons, all of which have homologues at the corresponding position in the ␣1-syntrophin gene. Primer extension analysis reveals two transcription initiation sites in the ␣1-syntrophin gene and a single site in the ␤2-syntrophin gene. The sequence immediately 5 of the transcription start sites of both genes lacks a TATA box but is GC-rich and has multiple putative SP1 binding sites. The ␣1-syntrophin gene is located on human chromosome 20 and mouse chromosome 2, while the ␤2-syntrophin gene is on human chromosome 16 and mouse chromosome 8. Analysis of the amino acid sequence of the syntrophins reveals the presence of four conserved domains. The carboxylterminal 56 amino acids are highly conserved and constitute a syntrophin unique domain. Two pleckstrin homology domains are located at the amino-terminal end of the protein. The first pleckstrin homology domain is interrupted by a domain homologous to repeated sequences originally found in the Drosophila discs-large protein.Syntrophin is a peripheral membrane protein of M r ϳ58,000 that was first identified in the postsynaptic membrane of Torpedo electric organ and subsequently shown to be present in many mammalian tissues (1). Interest in syntrophin came first from its location at the neuromuscular junction and more recently from the demonstration that it is directly associated with dystrophin, the product of the Duchenne/Becker muscular dystrophy gene. Although the precise function of syntrophin is unknown, a potential role for the dystrophin-associated proteins in agrin-stimulated nicotinic acetylcholine receptor clustering has implicated syntrophin in the process of synaptogenesis (2).Three different but highly conserved syntrophin isoforms encoded by distinct genes have been identified and cloned. Each syntrophin has approximately 50% amino acid identity with the other two (3). The three syntrophins can be separated into two classes based on isoelectric point (4). The acidic isoform, ␣1-syntrophin, (pI ϳ6.7) has been cloned from Torpedo, mouse, rabbit, and human (5-7). There are two basic forms, ␤1-and ␤2-syntrophin (pI ϳ 9.0). A full-length human cDNA encoding ␤1-syntrophin has been cloned, and the gene has been localized to human chromosome 8q23-24 (8). Partial clones encoding mouse and human ␤2-syntrophin have been reported previously (5,8).The function of syntrophin is likely to be related to its association with dystrophin and other members of the dystrophin protein family (9 -13). Proteins of the dystrophin family are derived from a combination of three genes, the use of alternative promoters within these genes, and alternative splicing. Dystrophin, the major product in skeletal muscle, is a 427-kDa protein with an actin-bi...

We recently cloned the cDNA which encodes a novel megakaryocyte-associated tyrosine kinase termed MATK. In this study, we have cloned and characterized the human MATK gene as well as the murine homolog of human MATK cDNA and performed functional studies of its translated product. Comparison of the deduced amino acid sequences of human and murine MATK cDNAs revealed 85% homology, indicating that MATK is highly conserved in mouse and human. The human gene consists of 13 exons interrupted by 12 introns. The genetic units which encode the SH3 and SH2 domains are located on separate exons. The putative ATP binding site (GXGXXG) is localized on exon 7, and the entire catalytic domain is subdivided into seven exons (7-13). Somatic cell hybrid analysis indicated that human MATK gene is located on chromosome 19 while the murine Matk gene is located on chromosome 10. The immediate 5'-flanking region was highly rich in GC sequences, and potential cis-acting elements were identified including several SP1, GATA-1, APRE, and APRE1. Antisense oligonucleotides directed against MATK mRNA sequences significantly inhibited megakaryocyte progenitor proliferation. Functional studies indicated that MATK can phosphorylate the carboxyl-terminal conserved tyrosine of the Src protein. These results support the notion that MATK acts as a regulator of p60c-src in megakaryocytic cells and participates in the pathways regulating growth of cells of this lineage.

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