Regulation of protein kinase CβI by two protein-tyrosine kinases, Btk and Syk

Regulation of protein kinase CβI by two protein-tyrosine kinases, Btk and Syk

^*Division of Allergy, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121; ^†Department of Laboratory Medicine, University of California, San Francisco, CA 94143; and ^‡Receptors and Signal Transduction Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research/National Institutes of Health, Bethesda, MD 20892

Communicated by Kimishige Ishizaka, Kirin Brewery Co., Ltd., Tokyo, Japan (received for review January 1, 2000)

Abstract

Two protein-tyrosine kinases, Bruton's tyrosine kinase (Btk) and Syk, and members of the protein kinase C (PKC) subfamily of serine/threonine kinases play crucial roles in signal transduction through antigen receptors in B lymphocytes and high-affinity IgE receptors (FcɛRI) in mast cells. The present study provides genetic, biochemical, and pharmacological evidence that, on FcɛRI stimulation, Syk regulates Btk, and Btk selectively regulates the membrane translocation and enzymatic activity of PKCβI among the conventional PKC isoforms (α, βI, and βII) expressed in mast cells. Syk/Btk-mediated PKCβI regulation is involved in transcriptional activation of the IL-2 and tumor necrosis factor α genes through the JNK pathway induced by FcɛRI stimulation. Accordingly, FcɛRI-induced production of these cytokines is inhibited by specific inhibitors of Btk and Syk, as well as broad-specificity inhibitors of PKC and a selective inhibitor of PKCβ. Specific regulation of PKCβI by Btk is consistent with the selective association of Btk with PKCβI. Components of this signaling pathway may represent an attractive set of potential targets of pharmaceutical interference for the treatment of allergic and other immunologic diseases.

Footnotes

↵ § To whom reprint requests should be addressed. E-mail: toshi_kawakami{at}liai.org.
Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.120175097.
Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.120175097
Abbreviations:

BCR,

B cell receptor;

Btk,

Bruton's tyrosine kinase;

DNP,

dinitrophenyl;

PKC,

protein kinase C;

FcɛRI,

high-affinity IgE receptors;

IP3,

inositol 1,4,5-trisphosphate;

PLC,

phospholipase C;

TNF,

tumor necrosis factor;

wt,

wild type;

xid,

X-linked immunodeficiency;

PMA,

phorbol 12-myristate 13-acetate;

HA,

hemagglutinin;

GST,

glutathione S-transferase