The protein product of the proto-oncogene c-cbl forms a complex with phosphatidylinositol 3-kinase p85 and CD19 in anti-IgM-stimulated human B-lymphoma cells.
Multiple signal transduction cascades, consisting of multiple interacting proteins, are activated following stimulation through most cell surface receptors, including the immunoglobulin receptor of B lymphocytes. In this report, we investigated the multimolecular complexes formed following anti-Ig stimulation of a human B-lymphoma cell line, resulting in activation of phosphatidylinositol 3-kinase (PI3K). PI3K is a lipid kinase that consists of an 85-kD regulatory subunit, bound to a 110-kD catalytic subunit. CD19 is a 95-kD B-cell surface marker that contains a consensus binding motif for PI3Kp85 in the cytoplasmic domain and recruits PI3K activity in activated B cells. The protein product of the c-cbl protooncogene is a 120-kD protein that is expressed in early B-lineage cells and in myeloid cells and is phosphorylated on tyrosine following receptor-mediated signaling in T and B lymphocytes. We demonstrate here that phosphorylated c-cbl complexes with CD19 and with PI3Kp85 via its C-terminal SH2 domain, and that both c-cbl and CD19 are associated with active PI3K in anti-Ig-stimulated cells. Although we cannot differentiate between a three-component, c-cbl/CD19/p85 complex and individual two-component complexes, these studies suggest that c-cbl may function as a docking protein, possibly linking distinct signal transduction pathways.
Intramural Research Support Program, SAIC/Frederick, Frederick Cancer Research and Development Center, MD, USA.
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Beckwith
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Jorgensen
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Longo
D018941:Antigens, CD19 / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology* / Q000494:pharmacology; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000276:immunology / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000276:immunology / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl; D011971:Receptors, Immunologic / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases
D018941:Antigens, CD19; D007075:Immunoglobulin M; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D050721:Proto-Oncogene Proteins c-cbl; D011971:Receptors, Immunologic; D044767:Ubiquitin-Protein Ligases; C000715470:MAS1 protein, human; C067419:CBL protein, human