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Requirement for Ras Guanine Nucleotide Releasing Protein 3 in Coupling Phospholipase C-2 to Ras in B Cell Receptor Signaling

Masatsugu Oh-hora¹, Sachiko Johmura¹, Ari Hashimoto¹, Masaki Hikida¹ and Tomohiro Kurosaki^1,2

¹ Department of Molecular Genetics, Institute for Liver Research, Kansai Medical University, Moriguchi 570-8506, Japan
² Laboratory for Lymphocyte Differentiation, RIKEN Research Center for Allergy and Immunology, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan

Address correspondence to Tomohiro Kurosaki, Dept. of Molecular Genetics, Institute for Liver Research, Kansai Medical University, Moriguchi 570-8506, Japan. Phone: 81-6-6993-9445; Fax: 81-6-6994-6099; email: kurosaki{at}mxr.mesh.ne.jp

Two important Ras guanine nucleotide exchange factors, Son of sevenless (Sos) and Ras guanine nucleotide releasing protein (RasGRP), have been implicated in controlling Ras activation when cell surface receptors are stimulated. To address the specificity or redundancy of these exchange factors, we have generated Sos1/Sos2 double- or RasGRP3-deficient B cell lines and determined their ability to mediate Ras activation upon B cell receptor (BCR) stimulation. The BCR requires RasGRP3; in contrast, epidermal growth factor receptor is dependent on Sos1 and Sos2. Furthermore, we show that BCR-induced recruitment of RasGRP3 to the membrane and the subsequent Ras activation are significantly attenuated in phospholipase C-2–deficient B cells. This defective Ras activation is suppressed by the expression of RasGRP3 as a membrane-attached form, suggesting that phospholipase C-2 regulates RasGRP3 localization and thereby Ras activation.

Key Words: DAG • PLC-2 • RasGRP3 • ERK • B cell activation

Abbreviations used in this paper: BCR, B cell receptor; BLNK, B cell linker; DAG, diacylglycerol; EGFP, enhanced green fluorescent protein; EGFR, epidermal growth factor receptor; GAP, GTPase-activating protein; GEF, guanine nucleotide exchange factor; GFP, green fluorescent protein; GST, glutathione S-transferase; GTPase, guanosine triphosphatase; MAPK, mitogen-activated protein kinase; PLC, phospholipase C; RasGRP, Ras guanine nucleotide releasing protein; SH, src homology; Sos, Son of sevenless.

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