TCR and CD28 are coupled via ZAP-70 to the activation of the Vav/Rac-1-/PAK-1/p38 MAPK signaling pathway

Kostantin V Salojin; Jian Zhang; Terry L Delovitch

doi:10.4049/jimmunol.163.2.844

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TCR and CD28 are coupled via ZAP-70 to the activation of the Vav/Rac-1-/PAK-1/p38 MAPK signaling pathway

Journal article

Peer reviewed

TCR and CD28 are coupled via ZAP-70 to the activation of the Vav/Rac-1-/PAK-1/p38 MAPK signaling pathway

Kostantin V Salojin, Jian Zhang and Terry L Delovitch

The Journal of immunology (1950), Vol.163(2), pp.844-853

07/15/1999

DOI: 10.4049/jimmunol.163.2.844

PMID: 10395678

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Abstract

CD28 costimulation amplifies TCR-dependent signaling in activated T cells, however, the biochemical mechanism(s) by which this occurs is not precisely understood. The small GTPase Rac-1 controls the catalytic activity of the mitogen-activated protein kinases (MAPKs) and cell cycle progression through G1. Rac-1 activation requires the phospho-tyrosine (p-Tyr)-dependent recruitment of the Vav GDP releasing factor (GRF) to the plasma membrane and assembly of GTPase/GRF complexes, an event critical for Ag receptor-triggered T cell activation. Here, we show that TCR/CD28 costimulation synergistically induces Rac-1 GDP/GTP exchange. Our findings, obtained by using ZAP-70-negative Jurkat T cells, indicate that CD28 costimulation augments TCR-mediated T cell activation by increasing the ZAP-70-mediated Tyr phosphorylation of Vav. This event regulates the Rac-1-associated GTP/GDP exchange activity of Vav and downstream pathway(s) leading to PAK-1 and p38 MAPK activation. CD28 amplifies TCR-induced ZAP-70 activity and association of Vav with ZAP-70 and linker for activation of T cells (LAT). These results favor a model in which ZAP-70 regulates the intersection of the TCR and CD28 signaling pathways, which elicits the coupling of TCR and CD28 to the Rac-1, PAK-1, and p38 MAPK effector molecules.

Phosphorylation

Protein Kinases - metabolism

T-Lymphocytes - enzymology

ras-GRF1

Protein-Tyrosine Kinases - metabolism

Humans

ZAP-70 Protein-Tyrosine Kinase

Phosphoproteins - metabolism

Proto-Oncogene Proteins - biosynthesis

Enzyme Activation - immunology

CD28 Antigens - metabolism

Protein-Tyrosine Kinases - physiology

Signal Transduction - immunology

Calcium-Calmodulin-Dependent Protein Kinases - biosynthesis

Proto-Oncogene Proteins c-vav

JNK Mitogen-Activated Protein Kinases

p38 Mitogen-Activated Protein Kinases

CD28 Antigens - physiology

Mitogen-Activated Protein Kinases

Proto-Oncogene Proteins - metabolism

Proto-Oncogene Proteins - antagonists & inhibitors

Adjuvants, Immunologic - physiology

Oligonucleotides, Antisense - pharmacology

GTPase-Activating Proteins

Receptors, Antigen, T-Cell - metabolism

Jurkat Cells

Calcium-Calmodulin-Dependent Protein Kinases - antagonists & inhibitors

Receptors, Antigen, T-Cell - physiology

Guanine Nucleotide Exchange Factors

Drug Synergism

Membrane Proteins

Adaptor Proteins, Signal Transducing

Tyrosine - metabolism

Animals

Carrier Proteins - metabolism

Proteins - metabolism

Down-Regulation - immunology

Mice

Mice, Inbred BALB C

Oligodeoxyribonucleotides - pharmacology

Calcium-Calmodulin-Dependent Protein Kinases - metabolism

Cell Cycle Proteins

Details

Title: Subtitle: TCR and CD28 are coupled via ZAP-70 to the activation of the Vav/Rac-1-/PAK-1/p38 MAPK signaling pathway
Creators: Kostantin V Salojin - Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, Department of Microbiology, University of Western Ontario, London, Canada
Jian Zhang
Terry L Delovitch
Resource Type: Journal article
Publication Details: The Journal of immunology (1950), Vol.163(2), pp.844-853
DOI: 10.4049/jimmunol.163.2.844
PMID: 10395678
NLM abbreviation: J Immunol
ISSN: 0022-1767
eISSN: 1550-6606
Publisher: United States
Language: English
Date published: 07/15/1999
Academic Unit: Pathology
Record Identifier: 9984047759102771

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