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 (original) (raw)
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The Journal of Experimental Medicine, 1998
B cell antigen receptor (BCR) cross-linking activates three distinct families of nonreceptor protein tyrosine kinases (PTKs): src-family kinases, Syk, and Btk; these PTKs are responsible for initiating downstream events. BCR cross-linking in the chicken DT40 B cell line also activates three distinct mitogen-activated protein kinases (MAPKs): extracellular signal–regulated kinase (ERK)2, c-jun NH2-terminal kinase (JNK)1, and p38 MAPK. To dissect the functional roles of these PTKs in MAPK signaling, activation of MAPKs was examined in various PTK-deficient DT40 cells. BCR-mediated activation of ERK2, although maintained in Lyn-deficient cells, was abolished in Syk-deficient cells and partially inhibited in Btk-deficient cells, indicating that BCR-mediated ERK2 activation requires Syk and that sustained ERK2 activation requires Btk. BCR-mediated JNK1 activation was maintained in Lyn-deficient cells but abolished in both Syk- and Btk-deficient cells, suggesting that JNK1 is activated vi...
BMC immunology, 2001
Bruton's tyrosine kinase (Btk) is essential for B cell development and function. Mutations of Btk elicit X-linked agammaglobulinemia in humans and X-linked immunodeficiency in the mouse. Btk has been proposed to participate in B cell antigen receptor-induced signaling events leading to activation of phospholipase C-gamma2 (PLCgamma2) and calcium mobilization. However it is unclear whether Btk activation is alone sufficient for these signaling events, and whether Btk can activate additional pathways that do not involve PLCgamma2. To address such issues we have generated Btk:ER, a conditionally active form of the kinase, and expressed it in the PLCgamma2-deficient DT40 B cell line. Activation of Btk:ER was sufficient to induce multiple B cell signaling pathways in PLCgamma2-sufficient DT40 cells. These included tyrosine phosphorylation of PLCgamma2, mobilization of intracellular calcium, activation of extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) ...
Phospholipase Cγ2 Is Essential in the Functions of B Cell and Several Fc Receptors
Immunity, 2000
A wide variety of substrates of tyrosine phosphoryla-1 Howard Hughes Medical Institute tion have been identified and, somewhat unexpectedly, 2 Department of Biochemistry many are phosphorylated in the responses to a wide 3 Department of Immunology variety of cytokines as well as in the responses to T 4 Division of Experimental Hematology cell, B cell, and Fc receptors. In addition, many are 5 Department of Infectious Diseases phosphorylated in the response to growth factors that St. Jude Children's Research Hospital utilize receptors of the family of tyrosine kinase recep-Memphis, Tennessee 38105 tors. Among these substrates are enzymes involved in 6 Department of Biochemistry inositol phosphate metabolism, including the regulatory University of Tennessee Medical School, Memphis subunit of phosphoinositide 3-kinase (PI3K) (Toker and Memphis, Tennessee 38063 Cantley, 1997). The importance of this pathway has been emphasized by the derivation of mice lacking the p85␣ gene (Fruman et al., 1999; Suzuki et al., 1999). Among Summary the defects that exist is a disruption of signaling through the B cell receptor, resulting in a phenotype that is simi-Many receptors activate phospholipase C␥1 or -␥2. To lar to that seen in mice lacking the tyrosine kinase Btk assess the role of PLC␥2, we derived enzyme-deficient (Kerner et al., 1995; Khan et al., 1995). mice. The mice are viable but have decreased mature Phosphatidylinositols are hydrolyzed by phospholi-B cells, a block in pro-B cell differentiation, and B1 B pases to generate diacyl-glycerol and inositol phoscell deficiency. IgM receptor-induced Ca 2؉ flux and phates including inositol 1,4,5-trisphosphate (IP 3 ) (Rhee proliferation to B cell mitogens are absent. IgM, IgG2a, and Bae, 1997). The diacyl-glycerol generated activates and IgG3 levels are reduced, and T cell-independent protein kinase C (PKC) family members, while IP 3 mediantibody production is absent. The similarity to Btkates the mobilization of Ca 2ϩ from internal stores, reor Blnk-deficient mice demonstrates that PLC␥2 is sulting in a transient intracellular Ca 2ϩ flux. Mammalian downstream in Btk/Blnk signaling. FcR␥ signaling is cells contain at least ten genes that encode phosphatialso defective, resulting in a loss of collagen-induced dylinositol 4,5-bisphosphate-specific phospholipase C platelet aggregation, mast cell Fc⑀R function, and NK isozymes (Rhee and Bae, 1997). The PLC- subfamily cell Fc␥RIII and 2B4 function. The results define a of enzymes (1-4) are stringently regulated by G proteinsignal transduction pathway broadly utilized by immucoupled receptors, while the PLC-␦ isoforms (1-4) are noglobulin superfamily receptors. regulated by largely unknown mechanisms, although Ca 2ϩ may be involved. The two PLC␥ isoforms ␥1 and ␥2 are unique in containing two SH2 domains, an SH3 Introduction domain, and a PH domain. The SH2 domains allow their recruitment to activated receptor complexes through Hematopoiesis is regulated through the concerted action of a variety of cytokine receptors and members of specific sites of tyrosine phosphorylation on receptor the immunoglobulin superfamily of receptors. Engagechains. The PH domain is speculated to be important ment of any of these receptor systems induces the actiin docking the enzyme to the inner membrane by bindvation of receptor-associated tyrosine kinases and subing PIP3. The activities of PLC␥1 and -␥2 are thought sequent induction of the tyrosine phosphorylation of a to be regulated through direct tyrosine phosphorylation variety of substrates, including the components of the (Nishibe et al., 1990), SH2-mediated conformational receptor. The functions of the cytokine receptor superchanges of the enzyme, or by physical recruitment to family are critically dependent upon the Jak family of the membrane-localized receptor complex. cytoplasmic protein tyrosine kinases (Ihle, 1995; Ihle and A wide variety of cytokines, tyrosine kinase receptors, Kerr, 1995; O'Shea, 1997). In contrast, the T cell and B and immunoglobulin superfamily receptors (TCR, BCR, cell antigen receptors as well as the complexes associand Fc receptors) induce the tyrosine phosphorylation of ated with signaling through Fc receptors are dependent PLC␥1 and/or PLC␥2. In particular, erythropoietin (Epo) upon members of the Src family of kinases, the Tec induces the tyrosine phosphorylation of both isoforms family of kinases, and the Zap70/Syk kinases (Paul and (Miura et al., 1994; unpublished data). Induction requires Seder, 1994; Weiss and Littman, 1994; Daeron, 1997; the distal region of the Epo receptor containing tyrosine residues that are required for recruitment to the receptor complex. In addition, we have found that both PLC␥1 7 To whom correspondence should be addressed (e-mail james.ihle@ and PLC␥2 bind to a major site of tyrosine phosphorystjude.org). lation within the kinase domain of Jak2 (unpublished 8
FEBS Letters, 2001
In this study, we examined the contribution made by CD45 to B cell antigen receptor (BCR)-induced activation of mitogen-activated protein kinase (MAPK) family members. We found that CD45 negatively regulated BCR-induced c-Jun NH 2terminal kinase (JNK) and p38 activation in immature WEHI-231 cells, whereas in mature BAL-17 cells, CD45 positively regulated JNK and p38 activation and negatively regulated extracellular signal-regulated kinase activity. Furthermore, cooperative action of JNK and p38 dictated BCR-induced inhibition of growth. Thus, CD45 appears to differentially regulate BCR-induced activation of MAPK members, and can exert opposing effects on JNK and p38 in different cellular milieu, controlling the B cell fate.
Journal of immunology (Baltimore, Md. : 1950), 1996
B cell antigen receptor (BCR)-induced apoptosis in the WEHI-231 B lymphoma cell line can be prevented by engaging CD40. We have used this cell line to investigate the role of mitogen-activated protein (MAP) kinases in integrating BCR and CD40 signaling. Each of the three types of MAP kinases, the extracellular signal-regulated kinases (ERKs), the c-Jun N-terminal kinases (JNKs), and p38, phosphorylates a distinct set of transcription factors. Thus, activating different combinations of MAP kinases could lead to distinct biological responses. We found that BCR engagement in WEHI-231 cells caused a 15- to 20-fold activation of ERK2 and a 2- to 3-fold stimulation of ERK1. CD40 did not activate either of these kinases, nor did it affect BCR-induced ERK activation. In contrast, CD40 engagement caused a 50- to 70-fold increase in JNK activity. BCR cross-linking caused a modest (4- to 8-fold) increase in JNK activity by itself and also potentiated CD40-induced JNK activation. Finally, CD40 ...