Differential coupling of membrane Ig and CD40 to the extracellularly regulated kinase signaling pathway.
Coupling of membrane Ig (mIg) and CD40 to the extracellularly regulated kinase (ERK) signal transduction pathway was examined in the WEHI-231 B lymphoma and normal mouse B cells. Cross-linking mIg induces ERK activation in both WEHI-231 and normal B cells. In contrast, CD40 cross-linking failed to induce ERK activation in WEHI-231, but signals through CD40 were more effective than mIg as a stimulus for ERK activation in normal B cells. However, several lines of evidence suggest that CD40 and the B cell Ag regulate ERK through distinct pathways that converge at the level of MEK-1, mitogen-activated protein kinase kinase. Abs to mIg or CD40 induced MEK-1 activation with different kinetics. Cross-linking of mIg, but not CD40, induced tyrosine phosphorylation of the SHC adapter molecule that couples receptors to Ras-dependent signaling pathways. Finally, agents that elevate cAMP, causing protein kinase A-mediated inhibition of Raf-1, inhibited activation of ERK in response to mIg cross-linking, but had no affect on ERK activation in response to anti-CD40 or Jun N-terminal kinase activation by signals through either receptor. Thus, CD40 uses an unidentified protein kinase A-insensitive MEK kinase, rather than Raf-1, to regulate ERK activity.
Purkerson
J M
JM
Department of Molecular Microbiology and Immunology, Oregon Health Sciences University, Portland 97201, USA.
Parker
D C
DC
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology; D019013:CD40 Antigens / Q000378:metabolism* / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D048031:JNK Mitogen-Activated Protein Kinases; D016393:Lymphoma, B-Cell; D048369:MAP Kinase Kinase 1; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism* / Q000502:physiology; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D019013:CD40 Antigens; D011506:Proteins; D011947:Receptors, Antigen, B-Cell; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014443:Tyrosine; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases