The protein product of the c-cbl protooncogene is the 120-kDa tyrosine-phosphorylated protein in Jurkat cells activated via the T cell antigen receptor.
Tyrosine phosphorylation of multiple cellular proteins is a critical event in T cell receptor (TCR)-mediated activation. This pathway has also been implicated in cellular transformation in multiple systems. The viral oncogene v-cbl is the transforming gene of a murine retrovirus that induces pre-B cell lymphomas and myelogenous leukemias. The product of its cellular homolog, p120cbl, is a 120-kDa cytoplasmic protein that is non-transforming when overexpressed. Here we show that the 120-kDa protein tyrosine phosphorylated in Jurkat T cells upon TCR engagement is p120cbl. Following stimulation through the TCR, this tyrosine phosphorylation is rapid and reversible. Tyrosine-phosphorylated p120cbl binds to glutathione S-transferase fusion proteins generated from SH2 domains of the Fyn, Lck, and Blk protein tyrosine kinases, GTPase-activating protein and phospholipase C gamma. The p120cbl from unactivated and activated cells also binds to full-length glutathione S-transferase-Grb2 and the Grb2 N-terminal SH3 domain, but not to the Grb2 C-terminal SH3 domain. Additionally, p120cbl binds to SH3 domains of Fyn and Lck, but not Blk. These data expand our knowledge of protein tyrosine kinase signaling pathways in T cells by identifying a prominent tyrosine kinase substrate. This protein, the product of the cellular homolog of a transforming oncogene, can interact with several known signaling molecules.
Donovan
J A
JA
Cell Biology and Metabolism Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892.
Wange
R L
RL
Langdon
W Y
WY
Samelson
L E
LE
D002460:Cell Line; D006801:Humans; D010766:Phosphorylation; D011233:Precipitin Tests; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D050721:Proto-Oncogene Proteins c-cbl; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D014443:Tyrosine; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; C067419:CBL protein, human