The SH3 domain-binding T cell tyrosyl phosphoprotein p120. Demonstration of its identity with the c-cbl protooncogene product and in vivo complexes with Fyn, Grb2, and phosphatidylinositol 3-kinase

T. Fukazawa, K. A. Reedquist, T. Trub, S. Soltoff, G. Panchamoorthy, B. Druker, L. Cantley, S. E. Shoelson, H. Band

Research output: Contribution to journalArticle

184 Scopus citations


Previously, we have identified p120 as a Fyn/Lck SH3 and SH2 domain- binding protein that is tyrosine phosphorylated rapidly after T cell receptor triggering. Here, we used direct protein purification, amino acid sequence analysis, reactivity with antibodies, and two-dimensional gel analyses to identify p120 as the human c-cbl protooncogene product. We demonstrate in vivo complexes of p120(cbl) with Fyn tyrosine kinase, the adaptor protein Grb2, and the p85 subunit of phosphatidylinositol (PI) 3-kinase. The association of p120(cbl) with Fyn and the p85 subunit of PI 3-kinase (together with PI 3-kinase activity) was markedly increased by T cell activation, consistent with in vitro binding of p120(cbl) to their SH2 as well as SH3 domains. In contrast, a large fraction of p120(cbl) was associated with Grb2 prior to activation, and this association did not change upon T cell activation. In vitro, p120(cbl) interacted with Grb2 exclusively through its SH3 domains. These results demonstrate a novel Grb2-p12(cbl) signaling complex in T cells, distinct from the previously analyzed Grb2-Sos complex. The association of p120(cbl) with ubiquitous signaling proteins strongly suggests a general signal transducing function for this enigmatic protooncogene with established leukemogenic potential but unknown physiological function.

Original languageEnglish (US)
Pages (from-to)19141-19150
Number of pages10
JournalJournal of Biological Chemistry
Issue number32
StatePublished - Jan 1 1995


ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this