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Involvement of Guanosine Triphosphatases and Phospholipase C-γ2 in Extracellular Signal–regulated Kinase, c-Jun NH2-terminal Kinase, and p38 Mitogen-activated Protein Kinase Activation by the B Cell Antigen Receptor

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


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)-γ2–deficient DT40 B cells, and expression of RasN17 in the PLC-γ2–deficient cells completely abrogated the ERK activation. The PLC-γ2 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-γ2–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

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Publisher: The Rockefeller University Press
OAI identifier: oai:pubmedcentral.nih.gov:2212492
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    1. (1992). A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction.
    2. (1992). Activation of the MAP kinase pathway by the protein kinase raf.
    3. (1998). Activation of the mitogen-activated protein kinase/extracellular signal–regulated kinase pathway by conventional, novel, and atypical protein kinase C isotypes.
    4. (1996). Activation-induced association of a 145-kDa tyrosine-phosphorylated protein with Shc and Syk in B lymphocytes and macrophages.
    5. (1993). Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation.
    6. (1994). B cell antigen receptor cross-linking induces phosphorylation of the p21ras oncoprotein activators SHC and mSOS1 as well as assembly of complexes containing SHC, GRB-2, mSOS1, and a 145-kDa tyrosine-phosphorylated protein.
    7. (1994). B cell antigen receptor cross-linking induces tyrosine phosphorylation and membrane translocation of a multimeric Shc complex that is augmented by CD19 co-ligation.
    8. (1994). B cell antigen receptor stimulation induces formation of a Shc-Grb2 complex containing multiple tyrosine-phosphorylated proteins.
    9. (1997). by the vav proto-oncogene product.
    10. (1998). Calcineurin preferentially synergizes with PKC-u to activate JNK and IL-2 promoter in T lymphocytes.
    11. (1998). CD19 as a membrane-anchored adaptor protein of B lymphocytes: costimulation of lipid and protein kinases by recruitment of Vav.
    12. CD19 of B cells as a surrogate kinase insert region to bind phophatidylinositol 3-kinase.
    13. (1996). CD40 ligation results in protein kinase C–independent activation of ERK and JNK in resting murine splenic B cells.
    14. (1997). Characterization of the B lymphocyte populations in Lyn-deficient mice and the role of Lyn in signal initiation and down-regulation.
    15. (1997). Co-ligation of the antigen and Fc receptors gives rise to the selective modulation of intracellular signaling in B cells. Regulation of the association of phosphatidylinositol 3-kinase and inositol 59-phosphatase with the antigen receptor complex.
    16. (1997). Counterregulation by the coreceptors CD19 and CD22 of MAP kinase activation by membrane immunoglobulin.
    17. (1994). Cross-linking of surface IgM stimulates the Ras/Raf-1/MEK/MAPK cascade in human B lymphocytes.
    18. (1997). Deletion of SHIP or SHP-1 reveals two distinct pathways for inhibitory signaling.
    19. (1997). Different nuclear signals are activated by the B cell receptor during positive versus negative signaling.
    20. (1998). Different protein tyrosine kinases are required for B cell antigen receptor–mediated extracellular signal–regulated kinase, c-Jun NH2-terminal kinase 1, and p38 mitogen-activated protein kinase activation.
    21. (1997). Differential activation of transcription factors induced by Ca21 response amplitude and duration.
    22. Differential Raf requirement for activation of mitogenactivated protein kinase by growth factors, phorbol esters, and calcium.
    23. (1993). Differential signaling through the Ig-a and Ig-b components of the B cell antigen receptor.
    24. (1982). Evidence for an IgD homologue on chicken lymphocytes.
    25. Genetic evidence for involvement of type 1, type 2 and type 3 inositol 1,4,5-trisphosphate receptors in signal transduction through the B-cell antigen receptor.
    26. (1996). Grap is a novel SH3-SH2-SH3 adaptor protein that couples tyrosine kinases to the Ras pathway.
    27. (1993). Grb2 mediates the EGF-dependent activation of guanine nucleotide exchange on Ras.
    28. (1993). Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2.
    29. (1997). Initiation and processing of signals from the B cell antigen receptor.
    30. (1996). Involvement of stress-activated protein kinase and p38 mitogen-activated protein kinase in mIgM-induced apoptosis of human B lymphocytes.
    31. (1998). LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation.
    32. (1998). Lyn-mediated down-regulation of B cell antigen receptor signaling: Inhibition of protein kinase C activation by Lyn in a kinase-independent fashion.
    33. (1996). Mitogen-activated protein kinase cascades and regulation of gene expression.
    34. (1997). Molecular mechanisms in B cell antigen receptor signaling.
    35. p21ras couples the T cell antigen receptor to extracellular signal–regulated kinase 2 in T lymphocytes.
    36. (1995). Requirement of phospholipase C-g2 activation in surface immunoglobulin M–induced B cell apoptosis.
    37. (1998). Requirement of tyrosine phosphatase SHP-1 and SHP-2 for PIR-B–mediated inhibitory signal.
    38. (1995). Rho family GTPases regulate p38 mitogen-activated protein kinase through the downstream mediator Pak1.
    39. (1992). Selective activation of p42 mitogen-activated protein (MAP) kinase in murine B lymphoma cell lines by membrane immunoglobulin cross-linking. Evidence for protein kinase C–independent and –dependent mechanisms of activation.
    40. Selective activation of the JNK signaling cascade and c-Jun transcriptional activity by the small GTPases Rac and Cdc42Hs.
    41. (1993). Sequence of a chicken cDNA encoding a GRB2 protein.
    42. (1997). Shc contains two Grb2 binding sites needed for efficient formation of complexes with SOS in B lymphocytes.
    43. (1998). SHIP modulates immune receptor responses by regulating membrane association of Btk.
    44. (1994). Signaling through CD19 activates a Vav/mitogen-activated protein kinase pathway and induces formation of a CD19/Vav/phosphatidylinositol 3-kinase complex in human B cell precursors.
    45. (1991). Stimulation of B-cells via the membrane immunoglobulin receptor or with phorbol myristate 13 acetate induces tyrosine phosphorylation and activation of a 42-kDa microtubule-associated protein-2 kinase.
    46. (1996). T cell antigen receptor signal transduction pathways.
    47. (1994). The B–cell antigen receptor complex: structure and signal transduction.
    48. (1997). The complexity of signaling pathways activated by the BCR.
    49. (1995). The membrane immunoglobulin receptor utilizes a Shc/Grb2/hSOS complex for activation of the mitogen-activated protein kinase cascade in a B-cell line.
    50. (1983). The nucleotide sequence of the chick cytoplasmic b-actin gene. Nucleic Acids Res.
    51. (1998). The paired Ig-like receptor PIR-B is an inhibitory receptor that recruits the protein-tyrosine phosphatase SHP-1.
    52. (1995). The Rho family GTPases RhoA, Rac1, and CDC42Hs regulate transcriptional activation by SRF.
    53. (1997). The role of a lymphoid-restricted, Grb2-like SH3-SH2-SH3 protein in T cell receptor signaling.
    54. (1992). The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling.
    55. (1994). Tyrosine kinases Lyn and Syk regulate B cell receptor-coupled Ca21 mobilization through distinct pathways.
    56. (1993). Tyrosine phosphorylation of CD19 in pre-B and mature B cells.
    57. (1995). Tyrosine phosphorylation of Shc is mediated through Lyn and Syk in B cell receptor signaling.
    58. (1997). Tyrosine phosphorylation of the vav proto-oncogene products links FceRI to the Rac1-JNK pathway.

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