INVOLVEMENT OF GUANOSINE TRIPHOSPHATASES AND PHOSPHOLIPASE C-GAMMA-2 IN EXTRACELLULAR SIGNAL-REGULATED KINASE, C-JUN NH2-TERMINAL KINASE, AND P38 MITOGEN-ACTIVATED PROTEIN-KINASE ACTIVATION BY THE B-CELL ANTIGEN RECEPTOR

Mitogen-activated protein (MAP) kinase family members, including extra cellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK ), and p38 MAP kinase, have been implicated in coupling the B cell ant igen receptor (BCR) to transcriptional responses. However, the mechani sms that lead to the activation of these MAP kinase family members hav e been poorly elucidated. Here we demonstrate that the BCR-induced ERK activation is reduced by loss of Grb2 or expression of a dominant-neg ative form of Ras, RasN17, whereas this response is not affected by lo ss of Shc. The inhibition of the ERK response was also observed in pho spholipase C (PLC)-gamma 2-deficient DT40 B cells, and expression of R asN17 in the PLC-gamma 2-deficient cells completely abrogated the ERK activation. The PLC-gamma 2 dependency of ERK activation was most like ly due to protein kinase C (PKC) activation rather than calcium mobili zation, since loss of inositol 1,4,5-trisphosphate receptors did not a ffect ERK activation. Similar to cooperation of Ras with PKC activatio n in ERK response, both PLC-gamma 2-dependent signal and GTPase are re quired for BCR-induced JNK and p38 responses. JNK response is dependen t on Rac1 and calcium mobilization, whereas p38 response requires Rad and PKC activation.