Role of protein kinase C in signal attenuation following T cell receptor engagement
UMass Chan Affiliations
Program in Molecular Medicine and the Department of Biochemistry and Molecular BiologyDocument Type
Journal ArticlePublication Date
1999-07-10Keywords
*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
Metadata
Show full item recordAbstract
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.Source
J Biol Chem. 1999 Jul 16;274(29):20244-50.
DOI
10.1074/jbc.274.29.20244Permanent Link to this Item
http://hdl.handle.net/20.500.14038/42413PubMed ID
10400642Related Resources
ae974a485f413a2113503eed53cd6c53
10.1074/jbc.274.29.20244
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