MAPKINASE - A 2ND SITE OF G-PROTEIN REGULATION OF B-CELL ACTIVATION VIA THE ANTIGEN RECEPTORS

Ligation of the antigen receptors on B cells transduces transmembrane signals leading to the induction of DNA synthesis. We now show that a pertussis toxin-sensitive heterotrimeric G-protein(s) of the G(i) clas s plays a key role in the regulation of surface immunoglobulin (sIg)-m ediated DNA synthesis in B cells. This site of G-protein regulation is distinct from that we have previously reported to govern the coupling of the antigen receptors on B cells to the phospholipase C-mediated h ydrolysis of phosphatidylinositol-4,5-bisphosphate. We have, moreover, identified a candidate target for this new G-protein regulation by sh owing that mitogen-activating protein kinase (MAPkinase) activity, whi ch plays a key role in the transduction of sig-mediated proliferative signals in B cells, is abrogated by pre-exposure to pertussis toxin th at covalently modifies and inactivates heterotrimeric G-proteins of th e G(i) class. Furthermore, our data suggest that this pertussis toxin- sensitive G-protein couples the antigen receptors to MAPkinase activat ion, at least in part, by regulating sig-coupling to Lyn, Syk and perh aps Blk and Fyn activity, results consistent with studies in other sys tems which show that classical G-protein-coupled receptors recruit suc h protein tyrosine kinases to tranduce MAPkinase activation. Interesti ngly, however, this G-protein plays no apparent role in the control of up-regulation of major histocompatibility complex class II expression on B cells, suggesting that such G-protein-regulated-tyrosine kinase and MAPkinase activation is not required for the induction of this bio logical response following antigen receptor ligation.