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 she adaptors, and the p85 subunit of phosphatidylinositol 3-kinase

Govindaswamy Panchamoorthy, Toru Fukazawa, Sachiko Miyake, Stephen Soltoff, Kris Reedquist, Brian Druker, Steve Shoelson, Lewis Cantley, Hamid Band

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Abstract

We and others have demonstrated that the c-cbl protooncogene 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 She, which prominently associated with Grb2, was detected in association with Cbl in activated B cells. Thus, Grb2 and She 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.

Original languageEnglish (US)
Pages (from-to)3187-3194
Number of pages8
JournalJournal of Biological Chemistry
Volume271
Issue number6
DOIs
Publication statusPublished - Feb 9 1996

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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