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Involvement of Guanosine Triphosphatases and Phospholipase C-2 in Extracellular Signal–regulated Kinase, c-Jun NH₂-terminal Kinase, and p38 Mitogen-activated Protein Kinase Activation by the B Cell Antigen Receptor

Ari Hashimoto^*, Hidetaka Okada^*, Aimin Jiang, Mari Kurosaki^*, Steven Greenberg, Edward A. Clark, and Tomohiro Kurosaki^*

From the ^* Department of Molecular Genetics, Institute for Liver Research, Kansai Medical University, Moriguchi 570-8506, Japan; the Department of Microbiology, University of Washington, Seattle, Washington 98195; and the Department of Medicine and Pharmacology, Columbia University College of Physicians and Surgeons, New York 10032

Mitogen-activated protein (MAP) kinase family members, including extracellular signal–regulated kinase (ERK), c-Jun NH₂-terminal kinase ( JNK), and p38 MAP kinase, have been implicated in coupling the B cell antigen receptor (BCR) to transcriptional responses. However, the mechanisms that lead to the activation of these MAP kinase family members have been poorly elucidated. Here we demonstrate that the BCR-induced ERK activation is reduced by loss of Grb2 or expression of a dominant-negative form of Ras, RasN17, whereas this response is not affected by loss of Shc. The inhibition of the ERK response was also observed in phospholipase C (PLC)-2–deficient DT40 B cells, and expression of RasN17 in the PLC-2–deficient cells completely abrogated the ERK activation. The PLC-2 dependency of ERK activation was most likely due to protein kinase C (PKC) activation rather than calcium mobilization, since loss of inositol 1,4,5-trisphosphate receptors did not affect ERK activation. Similar to cooperation of Ras with PKC activation in ERK response, both PLC-2–dependent signal and GTPase are required for BCR-induced JNK and p38 responses. JNK response is dependent on Rac1 and calcium mobilization, whereas p38 response requires Rac1 and PKC activation.

Key Words: mitogen-activated protein kinase family • Ras • Rac1 • protein kinase C • calcium

Abbreviations used: BCR, B cell antigen receptor; EGF, epidermal growth factor; ERK, extracellular signal–regulated kinase; GST, glutathione S-transferase; IP₃, inositol 1,4,5-triphosphate; JNK, c-Jun NH₂-terminal kinase; MAP, mitogen-activated protein; PKC, protein kinase C; PLC, phospholipase C.

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