ALPHA-2-CHIMERIN, AN SH2-CONTAINING GTPASE-ACTIVATING PROTEIN FOR THE RAS-RELATED PROTEIN P21RAC DERIVED BY ALTERNATE SPLICING OF THE HUMAN N-CHIMERIN GENE, IS SELECTIVELY EXPRESSED IN BRAIN-REGIONS AND TESTES

n-Chimerin (alpha1-chimerin) is a brain GTPase-activating protein (GAP) for the ras-related p21rac. We now report the occurrence of another form of chimerin, termed alpha2-chimerin. This is the product of an alternately spliced transcript of the human n-chimerin gene encoding an N-terminal SH2 (src homology 2) domain in addition to the phorbol ester receptor and GAP domains. Alpha1- and alpha2-chimerin mRNAs were expressed differently. In the rat brain, only alpha1-chimerin mRNA was expressed in cerebellar Purkinje cells, although both alpha1- and alpha2-chimerin mRNAs occurred in neurons in the cerebral cortex, hippocampus, and thalamus. Only alpha2-chimerin RNA was expressed in rat testes, in early pachytene spermatocytes. A 45-kDa SH2-containing chimerin corresponding to the alpha2 form was purified from rat brain. As with Escherichia coli 45-kDa recombinant alpha2-chimerin, purified brain alpha2-chimerin exhibited racGAP activity which was stimulated by phosphatidylserine. The recombinant SH2 domain bound several P-32-labelled phosphoproteins of PC12 cells, whose phosphorylation increased in response to trophic factors, including nerve growth factor. To examine the relationships of alpha1- and alpha2-chimerin transcripts, human genomic DNA clones were characterized. In alpha2-chimerin mRNA, a 3' splice acceptor site within exon 1 of alpha1-chimerin mRNA was used, replacing its 5' untranslated region and N-terminal coding sequence. The single human n-chimerin gene was mapped to chromosome 2q31-q32.1, colocalizing with the CRE-BP1 transcription factor gene (2q32). It contained several splice junctions conserved with the sequence-related protein kinase C and bcr genes. Alpha2-Chimerin is only the second SH2-containing GAP and the first example of an SH2 domain generated by alternate splicing.