p120 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

• Published in: The Journal of biological chemistry Vol. 271; no. 6; pp. 3187 - 3194
• Main Authors: Panchamoorthy, Govindaswamy, Fukazawa, Toru, Miyake, Sachiko, Soltoff, Stephen, Reedquist, Kris, Druker, Brian, Shoelson, Steve, Cantley, Lewis, Band, Hamid
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 09.02.1996
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.271.6.3187

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 p120 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.