Identification and characterization of a novel isoform of ß-chimaerins with nuclear localization

Abstract

Chimaerins are a family of GTPase-activating proteins (GAPs) composed of four members: α1- α2- β1-and β2-chimaerin. All chimaerin isoforms have a catalytic GAP domain, with selectivity for the Rac GTPase, and a C1 domain with structural homology to those of protein kinase C isoforms (PKCs) that binds DAG and phorbol esters. α2- and β2-chimaerin also have an N-terminal SH2 domain involved in heteromolecular interactions with phosphotyrosine proteins. Chimaerins are generated by alternative transcription of two diff erent genes; the CHN1 gene which encodes α1- and α2-chimaerin, and the CHN2 gene which encodes β1- and β2- chimaerin. Deregulation of the CHN2 gene has been associated with human pathologies such as mental disorders and breast cancer. This gene is located in the 7p15 locus, consists of 13 exons and has two start sites; one in exon 1 that renders β2-chimaerin, and one in intron 6 that renders the β1-chimaerin isoform. In addition, we have identifi ed a new isoform generated by alternative splicing, that we named β1-Δ7p chimaerin. This isoform is similar to β1-chimaerin but has a partial deletion of exon 7 that results in the loss of 4 amino acids from the C1 domain. The functional characterization of this isoform indicates that is unresponsive to DAG or phorbol esters and, surprisingly, shows a prominent nuclear localization. Our data suggest that loss of a nuclear export signal (NES) in β1-Δ7p is responsible for its nuclear localization. We also show that this chimaerin isoform regulates specifi c functions mediated by nuclear Rac.