Abstract
Stimulation of the T cell antigen receptor (TCR) induces tyrosine phosphorylation of numerous intracellular proteins. We have recently investigated the role of the adaptor protein Shb in the early events of T cell signaling and observed that Shb associates with Grb2, linker for activation of T cells (LAT) and the TCR zeta-chain in Jurkat cells. We now report that Shb also associates with phospholipase C-gamma1 (PLC-gamma1) in these cells. Overexpression of Src homology 2 domain defective Shb caused diminished phosphorylation of LAT and consequently the activation of mitogen-activated protein kinases was decreased upon TCR stimulation. In addition, the Shb mutant also blocked phosphorylation of PLC-gamma1 and the increase in cytoplasmic Ca(2+) following TCR stimulation. Nuclear factor for activation of T cells is a major target for Ras and calcium signaling pathways in T cells following TCR stimulation, and the overexpression of the mutant Shb prevented TCR-dependent activation of the nuclear factor for activation of T cells. Consequently, endogenous interleukin-2 production was decreased under these conditions. The results indicate a role for Shb as a link between the TCR and downstream signaling events involving LAT and PLC-gamma1 and resulting in the activation of transcription of the interleukin-2 gene.
Highlights
From the ‡Department of Medical Cell Biology, Box 571, Biomedicum, Uppsala University, S-75123 Uppsala, Sweden and the §Laboratory of Cellular and Molecular Biology, DBS, NCI, National Institutes of Health, Bethesda, Maryland 20892-4255
We have previously established a role for Shb in T cell antigen receptor (TCR) signaling by describing Src homology 2 (SH2) domain-dependent binding of Shb to the TCR -chain, phosphotyrosine binding (PTB) domain-dependent association of Shb to p36/38 linker for activation of T cells (LAT), and proline-rich/SH3 domain interactions with Grb2 [13, 14]
A number of signaling molecules are not phosphorylated in response to TCR engagement in cells expressing the Shb without a functional SH2 domain
Summary
Vol 274, No 39, Issue of September 24, pp. 28050 –28057, 1999 Printed in U.S.A. Requirement of the Src Homology 2 Domain Protein Shb for T Cell Receptor-dependent Activation of the Interleukin-2 Gene Nuclear Factor for Activation of T Cells Element in Jurkat T Cells*. We have recently investigated the role of the adaptor protein Shb in the early events of T cell signaling and observed that Shb associates with Grb, linker for activation of T cells (LAT) and the TCR -chain in Jurkat cells. Overexpression of Src homology 2 domain defective Shb caused diminished phosphorylation of LAT and the activation of mitogen-activated protein kinases was decreased upon TCR stimulation. The T cell response is initiated by the presentation of an antigen to the T cell receptor (TCR).1 This is followed by rapid phosphorylation of tyrosines on both the receptor itself and cytoplasmic proteins, the initiation of several signaling cascades, and subsequently the activation of interleukin-2 (IL-2) gene transcription and other T cell immune functions.
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