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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
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
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1999 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 274, no 39, 28050-28057 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
1999. Vol. 274, no 39, 28050-28057 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-89705DOI: 10.1074/jbc.274.39.28050PubMedID: 10488157OAI: oai:DiVA.org:uu-89705DiVA: diva2:161401
Available from: 2002-03-27 Created: 2002-03-27 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Shb and Its Homologues: Signaling in T Lymphocytes and Fibroblasts
Open this publication in new window or tab >>Shb and Its Homologues: Signaling in T Lymphocytes and Fibroblasts
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Stimulation of the T cell receptor (TCR) induces tyrosine phosphorylation of numerous intracellular proteins, leading to activation of the interleukin-2 (IL-2) gene in T lymphocytes. Shb is a ubiquitously expressed adapter protein, with the ability to associate with the T cell receptor and several signaling proteins in T cells, including: the TCR ζ-chain, LAT, PLC-γ1, Vav, SLP-76 and Gads. Jurkat T cells expressing Shb with a mutation in the SH2 domain, exhibited reduced phosphorylation of several proteins and abolished activation of the MAP kinases ERK1, ERK2 and JNK, upon CD3 stimulation. The TCR induced Ca2+ response in these cells was abolished, together with the activation of the IL-2 promoter via the transcription factor NFAT. Consequently, IL-2 production was also perturbed in these cells, compared to normal Jurkat T cells. Shb was also seen to associate with the β and γ chains of the IL-2 receptor, upon IL-2 stimulation, in T and NK cells. This association occurred between the Shb SH2 domain and Tyr-510 of the IL-2R β chain. The proline-rich domains of Shb were found to associate with the tyrosine kinases JAK1 and JAK3, which are important for STAT-mediated proliferation of T and NK cells upon IL-2 stimulation. Shb was also found to be involved in IL-2 mediated regulation of apoptosis. These findings indicate a dual role for Shb in T cells, where Shb is involved in both T cell receptor and IL-2 receptor signaling.

A Shb homologue, Shf was identified, and seen to associate with the PDGF-α-receptor. Shf shares high sequence homology with Shb and a Shd (also of the Shb family) in the SH2 domain and in four motifs containing putative tyrosine phosphorylation sites. When Shf was overexpressed in fibroblasts, these cells displayed significantly lower rates of apoptosis than control cells in the presence of PDGF-AA. These findings suggest a role for the novel adapter Shf in PDGF-receptor signaling and regulation of apoptosis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2002. 54 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1129
Keyword
Cell biology, Shb, T cell receptor, IL-2 receptor, PDGF receptor, cell signaling, adapter proteins, LAT, Vav, PLC-g1, SLP-76, JAK1, JAK3, Jurkat cells, T cells, NK cells, Apoptosis., Cellbiologi
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-1813 (URN)91-554-5260-4 (ISBN)
Public defence
2002-04-19, B21, BMC, Uppsala, 09:15
Opponent
Available from: 2002-03-27 Created: 2002-03-27Bibliographically approved

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Gylfe, ErikWelsh, Michael

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