KINASE-INACTIVE SPLICE VARIANTS OF THE ACTIVIN TYPE I RECEPTOR

摘要

A ligand-induced heterodimeric complex of type I and II serine/ threonine kinase receptors in which the type I kinase is transphos-phorylated by the type II kinase mediates the biological activities of members of the TGFbeta family (Mathews and Vale,1991; Attisano et al., 1992; Attisano et al., 1993; Ebner et al., 1993; Tsuchida et al., 1993; ten Dijke et al., 1994; Xu et al., 1995). Two type I serine/ threonine kinase receptors, SKR1 (Matsuzaki et al., 1993) and SKR2 (Xu et al., 1994) were first cloned from a well-differentiated human hepatoma cell (HepG2) and subsequently shown to bind activin, a member of the TGFP ligand family, and elicit biological responses in concert with an activin type II receptor (ActRII) and activin (Attisano et al., 1993; Carcamo et al., 1994; ten Dijke et al., 1994; Xu et al., 1995). Alternative splicing and poly(A) addition within introns at the 3'-end of the last two coding exons 9a and lOa for the full-length COOH-terminus of SKR2 (SKR2-1) results in variants predicted to be devoid of kinase subdomains X and XI (SKR2-3) and XI (SKR2-2), respectively (Xu et al., 1994). According to the ge-nomic structure, an additional variant (SKR2-4) which lacks the coding sequence for kinase subdomains VIII-XI (Nishimatsu et al., 1992; Xu et al., 1994) could arise by the same mechanism. Here we report a fifth variant of the SKR2 mRNA (SKR2-5) that arises by alternate splicing of exon 9a whose product would be devoid of kinase subdomains VIII-XI. In several human cell lines, the SKR2-5 mRNA is expressed in quantities greater than those of all other SKR2 variants. Of the recombinant products of SKR2 variant mRNAs, only SKR2-1 exhibits kinase activity.