[Frontiers in Bioscience 7, d918-969, April 1, 2002]

PROTEIN TYROSINE PHOSPHORYLATION IN T CELL SIGNALING

Tomas Mustelin1, Robert T. Abraham1, Christopher E. Rudd2 , Andres Alonso1 & Joseph J. Merlo1

1Program of Signal Transduction, Cancer Research Center, The Burnham Institute, La Jolla, CA 92037, 2Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Department of Pathology, Harvard Medical School, Boston MA 02115

TABLE OF CONTENTS

1. Abstract
2. Introduction
2.1. Inositol phospholipid hydrolysis and calcium mobilization
2.2. TCR-induced tyrosine phosphorylation
3. Src-related kinases in T cells
3.1. Lck - a co-receptor associated PTK
3.2. Fyn - a Src-family PTK associated with the TCR complex.
3.3. c-Yes, the third and least understood Src-related kinase in T cells
3.4. Structure and Regulation of Src family PTKs
3.4.1. Lipid modification and lipid raft association of Lck and Fyn
3.4.2. Unique N-Terminal Region
3.4.3. SH3 Domain
3.4.4. SH2 Domain
3.4.5. Kinase Domain
3.5. Regulation of Src-family PTKs
3.5.1. Positive regulation by tyrosine phosphorylation in the kinase domain
3.5.2. Dephosphorylation of the activation loop tyrosine.
3.5.3. Regulatory C-terminus
3.5.4. Suppression of Src family kinases by Csk
3.5.5. Csk is opposed by CD45
3.5.6. Additional phosphorylation events
3.5.7. Src family PTKs and viruses
4. Syk-family PTKs in T cells
4.1. Regulatory mechanisms for Zap-70
4.2. Regulation of Syk
4.3. Both Zap-70 and Syk act as docking proteins
5. Structure and function of the Tec-family PTKs in T cells
5.1. Other tyrosine kinases in T cells
6. Protein tyrosine phosphatases in T cell activation
6.1. PTPases present in T lymphocytes
6.2. Role of CD45 in T cell activation
6.3. HePTP - in control of MAP kinases
6.4. SHP1 - mediator of inhibitory signaling
6.5. SHP2 in T cell activation
6.6. PEP - a partner of Csk in suppression of TCR signaling
6.7. PTP-MEG2 - a regulator of secretory vesicles
6.8. ERM-PTPases - gatekeepers at the membrane-cytoskeleton interface
6.9. PTEN - in control of lymphocyte life and death
6.10. LMPTP - a small and peculiar enzyme
7. Initiation of the TCR signaling cascade
7.1. ITAM phosphorylation by Src family PTKs
7.2. Which PTPase dephosphorylates the ITAMs?
7.3. Consequences of ITAM phosphorylation
7.4. Multiple ITAMs - redundancy, amplification or sensitivity?
7.5. Partial TCR-zeta phosphorylation and T cell anergy
7.6. The role of CD4 and CD8 in the initiation of T cell activation
7.7. Role of lipid rafts in TCR signaling
7.8. Nonredundant functions of Fyn(T)
7.9. Does Syk participate in T cell activation?
8. Substrates for kinases and phosphatases: enzymes, adapters and downstream signaling pathways
8.1. PLC-gamma1
8.2. LAT
8.3. SLP-76
8.4. FYB/SLAP-130, now called ADAP
8.5. Ras activation
8.6. Vav-1
8.7. PI3K
8.8. c-Cbl
8.9. TSAd
8.10. SAP/SH2D1A
8.11. TRIM
8.12. Other PTK substrates
9. Concluding remarks
10. Acknowledgements
11. References

1. ABSTRACT

This review discusses in considerable detail the tyrosine phosphorylation events that couple the T cell antigen receptor to downstream signaling pathways. First, the protein kinases that catalyze these tyrosine phosphorylation are introduced, then the phosphatases that mediate removal of phosphate from tyrosine residues. Next, we discuss the molecular clock work by which these enzymes initiated T cell activation. Finally, we briefly review the key substrates for tyrosine phosphorylation and their role in coupling the kinases and phosphatases to gene transcription and other aspects of the T lymphocyte response to antigen.