Biological Validation of the CD45 Tyrosine Phosphatase as a Pharmaceutical Target

D. R. Alexander

Laboratory of Lymphocyte Signalling and Development, The Babraham Institute,

Babraham, Cambridge, CB2 4AT, UK

[email protected]

1 Introduction 264

2 CD45 Regulates Receptor Thresholds 264

2.1 CD45 and Lymphocyte Development 264

2.2 CD45 and Lymphocyte Function 267

2.3 CD45 and Macrophages 267

2.4 CD45 and Mast Cells 268

2.5 CD45 and Natural Killer Cells 268

3 CD45 Substrates 269

3.1 The Src Tyrosine Kinases 269

3.2 Other Possible CD45 Substrates 273

4 CD45 Isoforms 274

4.1 The Exogenous Ligand Model 276

4.2 The Size Exclusion Model 276

4.3 The Cis-Cis Interaction Model 277

4.4 The Homodimerisation Model 278

5 CD45 as a Therapeutic Target 280

5.1 The Use of CD45 Monoclonal Antibodies 281

5.2 The Use of Chemical Inhibitors 283

5.3 Other Possible Approaches to Perturbing CD45 284

6 Conclusions 285

References 285

Abstract The CD45 phosphotyrosine phosphatase is expressed on all nucleated haematopoietic cells and plays an important role in regulating immune receptor signalling thresholds. CD45 substrates include Src tyrosine kinase family members, and in T cells both p56lck and p59fyn are substrates. Src kinases such as p56lck have negative regulatory C-terminus Tyr phosphorylation sites that are phosphorylated by the c-Src kinase and de-phosphorylated by CD45, thereby switching p56lck into a fully functional mode. Active p56lck, and to a lesser extent p59fyn, are involved in coupling the T cell antigen receptor to the intracellular signalling pathways that lead to T cell development and activation. In CD45_/_ mice, the threshold for receptor signalling is high and there are significant defects in thymic development resulting in a greater than 90% reduction in the repertoire of mature peripheral T cells. Those CD45_/_ T cells that do exit to the periphery are markedly non-responsive to mitogens. The p56lck kinase also has an activating autophosphorylation site that can be dephosphorylated by CD45 under some circumstances. However, the overall regulatory actions of CD45 on p56lck function in the context of T cell antigen receptor coupling are positive, and this is confirmed by restoration of the CD45_/_ phenotype with the lckY505F transgene. Up to eight CD45 isoforms are generated by alternative splicing of which at least five are expressed on lymphocytes at significant levels. Differential CD45 isoform expression is tightly controlled during lymphocyte development and activation, but putative differences in the molecular actions of the different isoforms remain poorly understood. CD45 is an attractive therapeutic target as a means to suppress T cell activation, of relevance in autoimmunity, protection against organ graft rejection and inflammation. CD45 may also be of use in cancer therapies. Current therapeutic strategies utilise CD45 monoclonal antibodies or phosphatase inhibitors. Increasing knowledge of CD45 structure and function will facilitate a more systematic and rational approach to drug design.

Keywords CD45 ■ Tyrosine phosphatase ■ Inhibitor ■ CD45 isoform ■ Monoclonal antibody

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