Genetic evidence for Shc requirement in TCR-induced c-Rel nuclear translocation and IL-2 expression

doi:10.1073/pnas.082647499

Genetic evidence for Shc requirement in TCR-induced c-Rel nuclear translocation and IL-2 expression

^*Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 30912-2600; ^‡Mitsubishi Kagaku Institute of Life Sciences, Machida, Tokyo 194-8511, Japan; and ^§Department of Molecular Genetics, School of Medicine, Chiba University, Chiba 260-8670, Japan

Edited by James P. Allison, University of California, Berkeley, CA, and approved January 30, 2002 (received for review December 4, 2001)

Abstract

Shc, a prototypic adapter molecule, has been implicated in T cell receptor (TCR) signal transduction, but its role has not been identified clearly. Here we report that Shc is essential for TCR-induced IL-2 production but is dispensable for CD69 or CD25 expression. Engagement of TCR in mutant Jurkat T cells lacking Shc fails to produce IL-2 because of impaired mitogen-activated protein kinase activation. Activation of c-Rel, a transcription factor essential for IL-2 expression, was impaired also. In contrast, activation of nuclear factor of activated T cell and expression of CD69/CD25 were comparable between the mutant and wild-type Jurkat cells. These defects were rescued by expression of exogenous Shc. Activation of c-Rel using the estrogen receptor fusion protein restored the activation of the IL-2 promoter in an estrogen-dependent manner. These results show that Shc plays an essential role in the TCR-induced activation of c-Rel and the IL-2 promoter.

Footnotes

↵ † To whom reprint requests should be addressed at: Institute of Molecular Medicine and Genetics, CB2803, Medical College of Georgia, 1120 15th Street, Augusta, GA, 30912-2600. E-mail: makio{at}immag.mcg.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

TCR,

T cell receptor;

ITAM,

immunoreceptor tyrosine-based activation motif;

PLCγ-1,

phospholipase Cγ-1;

ERK,

extracellular response kinase;

MEK,

mitogen-activated protein kinase kinase;

PMA,

phorbol 12-myristate 13-acetate;

ER,

estrogen receptor;

MAPK,

mitogen-activated protein kinase