title: Expression of the Grb2-related protein of the lymphoid system in B cell subsets enhances B cell antigen receptor signaling through mitogen-activated protein kinase pathways.
abstract: Adapter proteins play a critical role in regulating signals triggered by Ag receptor cross-linking. These small molecules link receptor proximal events with downstream signaling pathways. In this study, we explore the expression and function of the Grb2-related protein of the lymphoid system (GrpL)/Grb2-related adaptor downstream of Shc adapter protein in human B cells. GrpL is expressed in naive B cells and is down-regulated following B cell Ag receptor ligation. By contrast, germinal center and memory B cells express little or no GrpL. Using human B cell lines, we detected constitutive interactions between GrpL and B cell linker protein, Src homology (SH)2 domain-containing leukocyte protein of 76 kDa, hemopoietic progenitor kinase 1, and c-Cbl. The N-terminal SH3 domain of GrpL binds c-Cbl while the C-terminal SH3 domain binds B cell linker protein and SH2 domain-containing leukocyte protein of 76 kDa. Exogenous expression of GrpL in a GrpL-negative B cell line leads to enhanced Ag receptor-induced extracellular signal-related kinase and p38 mitogen-activated protein kinase phosphorylation. Thus, GrpL expression in human B cell subsets appears to regulate Ag receptor-mediated signaling events.
authors.affiliation: Department of Microbiology, University of Washington, Seattle WA 98195, USA. tyankee@u.washington.edu
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Yankee
authors.forename: Sasha A
authors.initials: SA
authors.lastname: Solow
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Draves
authors.forename: Edward A
authors.initials: EA
authors.lastname: Clark
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000276:Adjuvants, Immunologic / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D051380:GRB2 Adaptor Protein; D006801:Humans; D007399:Interphase / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000276:immunology*; D016297:Mutagenesis, Site-Directed; D014066:Palatine Tonsil; D010750:Phosphoproteins / Q000378:metabolism; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases; D018909:src Homology Domains / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000276:Adjuvants, Immunologic; C113939:B cell linker protein; D002352:Carrier Proteins; C409587:GRAP2 protein, human; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011947:Receptors, Antigen, B-Cell; C092947:SLP-76 signal Transducing adaptor proteins; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; C102102:hematopoietic progenitor kinase 1; D017346:Protein Serine-Threonine Kinases; C067419:CBL protein, human