p120cbl is a major substrate of tyrosine phosphorylation upon B cell antigen receptor stimulation and interacts in vivo with Fyn and Syk tyrosine kinases, Grb2 and Shc adaptors, and the p85 subunit of phosphatidylinositol 3-kinase.
We and others have demonstrated that the c-cbl proto-oncogene product is one of the earliest targets of tyrosine phosphorylation upon T cell receptor stimulation. Given the similarities in the B and T lymphocyte antigen receptors, and the induction of pre-B leukemias in mice by the v-cbl oncogene, we examined the ... potential involvement of Cbl in B cell receptor signaling. We demonstrate prominent and early tyrosine phosphorylation of Cbl upon stimulation of human B cell lines through surface IgM. Cbl was associated in vivo with Fyn and, to a lesser extent, other Src family kinases. B cell activation also induced a prominent association of Cbl with Syk tyrosine kinase. A substantial fraction of Cbl was constitutively associated with Grb2 and this interaction was mediated by Grb2 SH3 domains. Tyrosine-phosphorylated Shc, which prominently associated with Grb2, was detected in association with Cbl in activated B cells. Thus, Grb2 and Shc adaptors, which associate with immunoreceptor tyrosine based activation motifs, may link Cbl to the B cell receptor. B cell activation also induced a prominent association between Cbl and the p85 subunit of phosphatidylinositol (PI) 3-kinase resulting in the association of a substantial fraction of PI 3-kinase activity with Cbl. Thus, Cbl is likely to play an important role to couple the B cell receptor to the PI 3-kinase pathway. Our results strongly suggest a role for p120cbl in signaling downstream of the B cell receptor and support the idea that Cbl participates in a general signal transduction function downstream of the immune cell surface receptors.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, B-Lymphocytes, Cell Line, Enzyme Precursors, GRB2 Adaptor Protein, Glutathione Transferase, Humans, Intracellular Signaling Peptides and Proteins, Leukemia, B-Cell, Macromolecular Substances, Mice, Oncogene Protein v-cbl, Oncogenes, Phosphatidylinositol 3-Kinases, Phosphorylation, Phosphotransferases (Alcohol Group Acceptor), Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-fyn, Receptors, Antigen, B-Cell, Recombinant Fusion Proteins, Retroviridae Proteins, Oncogenic, src Homology Domains
Adaptor Proteins, Signal Transducing, Animals, B-Lymphocytes, Cell Line, Enzyme Precursors, GRB2 Adaptor Protein, Glutathione Transferase, Humans, Intracellular Signaling Peptides and Proteins, Leukemia, B-Cell, Macromolecular Substances, Mice, Oncogene Protein v-cbl, Oncogenes, Phosphatidylinositol 3-Kinases, Phosphorylation, Phosphotransferases (Alcohol Group Acceptor), Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-fyn, Receptors, Antigen, B-Cell, Recombinant Fusion Proteins, Retroviridae Proteins, Oncogenic, src Homology Domains
J. Biol. Chem.
Date: Feb. 09, 1996
PubMed ID: 8621719
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