TBE BMX TYROSINE KINASE INDUCES ACTIVATION OF THE STAT SIGNALING PATHWAY, WHICH IS SPECIFICALLY INHIBITED BY PROTEIN-KINASE C-DELTA

Members of the hematopoietically expressed Tec tyrosine kinase family have an important role in hematopoietic signal transduction, as exempl ified by the crucial role of Btk for B-cell differentiation and activa tion. Although a variety of cell surface receptors have been found to activate Tec tyrosine kinases, the specific signaling pathways and sub strate molecules used by Tec kinases are still largely unknown. In thi s study a Tec family kinase, Bmx, was found to induce activation of th e Stat signaling pathway. Bmx induced the tyrosine phosphorylation and DNA binding activity of all the Stat factors tested, including Stat1, Stat3, and Stat5, both in mammalian and insect cells. Bmx also induce d transcriptional activation of Stat1- and Stat5-dependent reporter ge nes. Other cytoplasmic tyrosine kinases, Syk, Fyn, and c-Src, showed n o or only weak ability to activate Stat proteins. Expression of Bmx in mammalian cells was found to induce activation of endogenous Stat pro teins without activation of endogenous Jak kinases. We further analyze d the Bmx-mediated activation of Stat1, which was found to be regulate d by protein kinase C delta (PKC delta) isoform, but not beta 1, epsil on, or zeta isoforms, leading to inhibition of Stat1 tyrosine phosphor ylation. In conclusion, these studies show that Bmx, a Tec family kina se, can function as an activator of the Stat signaling pathway and ide ntify a role for PKC delta in the regulation of Bmx signaling. (C) 199 7 by The American Society of Hematology.