Positive and negative regulation of Src-family membrane kinases by CD45

doi:10.1016/S0167-5699(99)01506-6

Immunology Today

Volume 20, Issue 9, 1 September 1999, Pages 406-411

Immunology Today

https://doi.org/10.1016/S0167-5699(99)01506-6 Get rights and content

Abstract

CD45 is a protein tyrosine phosphatase that functions to regulate Src-family kinases. However, in some instances CD45 is a positive regulator of kinase activity whereas in others, it is a negative regulator. Here, Matthew Thomas and Eric Brown discuss this paradox and suggest a mechanism by which CD45 can be both a positive and negative regulator of kinase activity simultaneously.

Section snippets

Regulation of Src-family kinases

In leukocytes, CD45 is an important regulator of Src-family kinases. The Src-family is a group of intracellular tyrosine kinases that interact with cell membranes via lipid modification and amino acids at the amino-terminus. However, interaction with specific receptors is mediated by protein–protein interactions. Each of the nine known family members comprises five regions: (1) an N-terminal region that is highly divergent between family members; (2) an Src-homology 2 (SH2) domain; (3) an SH3

CD45 is required for antigen receptor signal transduction

There are two biological functions that are clearly dependent on CD45. First, and most carefully examined, is antigen-receptor-mediated signal transduction. CD45-deficient cells are unable to efficiently activate signaling either in response to antigen or direct receptor cross-linking5, 12, 13, 14. Analysis of these cell lines demonstrates that the abnormality in antigen-receptor signaling correlates with a defect in regulation of the Src-family kinases4, 15, 16. Where examined, all

CD45 regulates integrin-mediated adhesion

The second biological function described for CD45 is the regulation of integrin-mediated adhesion. Integrins are a family of heterodimeric membrane proteins that act as receptors for cell and extracellular matrix (ECM) ligands. A very important characteristic of integrins produced by bone marrow-derived cells is that they are poor mediators of cell adhesion in the absence of activation. Teleologically, this provides a mechanism by which these cells can release from the bone marrow and circulate

Kinase activity during adhesion

CD45-deficient macrophages with abnormal integrin-mediated adhesion also show dysregulation of Src-family kinases. Both Lyn and Hck have increased kinase activity in CD45-deficient macrophages³. As both Lyn and Hck have been implicated in the regulation of integrin-mediated contacts, dysregulation of these kinases can account for the increased adhesion initially observed in CD45-deficient macrophages. In this context, CD45 becomes a negative regulator of Src-family kinases associated with

Positive and negative regulation of Src kinases by CD45

CD45 continuously controls Src-family member kinases by opposing Csk action and dephosphorylating the C-terminal tyrosine in both macrophages and lymphocytes. In addition, CD45 is capable of dephosphorylating the autophosphorylation site of Src-family kinases and thus decreasing kinase activity3, 4, 5. CD45 and Csk are constitutively active enzymes and, therefore, during steady state continuously oppose the actions of the other at the inhibitory site in Src-family kinases40, 41, 42.

Conclusion

We suggest that receptor engagement results in a dynamic redistribution of membrane proteins such that CD45 is included in focal adhesion sites, but excluded from engaged antigen receptors. Inclusion or exclusion from a site of receptor engagement results in CD45 functioning as either a positive or a negative regulator of Src-family kinases associated with that receptor. A critical question concerning the net effect of CD45 on Src-family kinase function in any biological context is the

Acknowledgements

We thank E. Fisher, P. Majerus and T. Woodford-Thomas for comments and suggestions on the manuscript. Our laboratory collegues provided many interesting discussions and results provoking the model presented here. Our work is supported by the NIH. M.L.T. acknowledges support from the Human Frontiers Science Program. M.L.T. is an investigator of the Howard Hughes Medical Institute.

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ViewpointPositive and negative regulation of Src-family membrane kinases by CD45

Abstract

Section snippets

Regulation of Src-family kinases

CD45 is required for antigen receptor signal transduction

CD45 regulates integrin-mediated adhesion

Kinase activity during adhesion

Positive and negative regulation of Src kinases by CD45

Conclusion

Acknowledgements

Curr. Biol.

J. Biol. Chem.

Curr. Opin. Cell Biol.

Curr. Opin. Cell Biol.

Cell

Curr. Opin. Immunol.

Curr. Opin. Cell Biol.

Cell. Immunol.

J. Biol. Chem.

J. Biol. Chem.

Immunity

Blood

Biochem. Biophys. Res. Commun.

Annu. Rev. Immunol.

Annu. Rev. Immunol.

Mol. Cell. Biol.

Src Family Tyrosine Kinases in Leukocytes

Nature

Nature

Nature

Nature

Trends Cell Biol.

Nature

Viewpoint
Positive and negative regulation of Src-family membrane kinases by CD45