Brk, Srm, Frk, and Src42A form a distinct family of intracellular Src-like tyrosine kinases

Abstract

The tyrosine kinases Brk/PTK6/Sik, Srm, Frk/Rak/Gtk/Iyk/Bsk, and Src42A/Dsrc41 have a low degree of sequence homology to other known kinases, including one another. We show here that the exon structure of these kinases, which we will call the Brk family, is highly conserved and distinct from each of the major families of intracellular kinases containing SH3, SH2, and tyrosine kinase domains, including c-Src and Fyn. Brk/Sik and Srm are 1.1 kb apart on human chromosome 20q13.3 and likely are the result of duplication in cis. Several Brk family kinases have an inhibitory effect on Ras pathway signaling from receptor tyrosine kinases. Members of this family can act either in the membrane or at the nucleus, and may change localization patterns depending on external stimuli. Brk has been shown to phosphorylate two proteins in vivo: Sam68. a substrate for Src in mitosis that can substitute for Rev in nuclear export of RNAs; and BKS, a novel adaptor molecule. Brk also functions as a rapid downstream signaling intermediate following calcium-induced differentiation in keratinocytes. It is possible that Brk family kinases may share common functions and interaction partners, which remain for the most part unexamined.