Role of protein kinase C in signal attenuation following T cell receptor engagement

UMMS Affiliation

Program in Molecular Medicine and the Department of Biochemistry and Molecular Biology

Publication Date


Document Type



*Adaptor Proteins, Signal Transducing; *Adaptor Proteins, Vesicular Transport; Animals; Humans; Jurkat Cells; Lymphocyte Activation; Mice; Oncogene Protein v-cbl; Protein Kinase C; Protein Kinases; Proteins; Receptors, Antigen, T-Cell; Retroviridae Proteins, Oncogenic; Signal Transduction; T-Lymphocytes; Tetradecanoylphorbol Acetate; Tyrosine


Life Sciences | Medicine and Health Sciences


T lymphocyte activation through stimulation of the T cell receptor complex and co-stimulatory receptors is associated with acute tyrosine phosphorylation of intracellular proteins, which in turn mediate downstream signaling events that regulate interleukin-2 expression and cell proliferation. The extent of protein tyrosine phosphorylation is rapidly attenuated after only 1-2 min of stimulation as a means of tightly controlling the initial signaling response. Here we show that this attenuation of tyrosine phosphorylation of Shc, CrkL, and the proto-oncogene Cbl is mimicked by treatment of mouse T lymphocytes or cultured Jurkat cells with phorbol 12-myristate 13-acetate. This effect is blocked by the specific protein kinase C inhibitor GF109203X, but not by PD98059, an inhibitor of MEK1/2 kinase. Activation of protein kinase C by phorbol ester also causes rapid (t(1)/(2) = 2 min) dissociation of both CrkL and p85/phosphoinositide 3-kinase from Cbl concomitant with Cbl tyrosine dephosphorylation. More important, GF109203X treatment of Jurkat cells prior to T cell receptor stimulation by anti-CD3/CD4 antibodies results in an enhanced (2-fold) peak of Cbl phosphorylation compared with that observed in control cells. Furthermore, the rate of attenuation of both Cbl tyrosine phosphorylation and its association with CrkL following stimulation with anti-CD3/CD4 antibodies is much slower in Jurkat cells treated with GF109203X. Taken together, these data provide strong evidence that one or more isoforms of phorbol ester-responsive protein kinase C play a key role in a feedback mechanism that attenuates tyrosine phosphorylation of proteins and reverses formation of signaling complexes in response to T cell receptor activation.

DOI of Published Version



J Biol Chem. 1999 Jul 16;274(29):20244-50.

Journal/Book/Conference Title

The Journal of biological chemistry

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PubMed ID