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Marion H. Brown |
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Outline of |
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The functional consequences of engagement of leukocyte surface receptors depend on coordination of extracellular and intracellular interactions. By studying selected receptors I aim to reveal both the specific niche the receptors occupy and the general paradigms. To understand how a receptor works, we dissect the molecular interactions. We developed methods for detecting low affinity interactions at the cell surface which led to the identification of the CD200/CD200R, CD47/SIRPa and CD48/2B4 interactions. More recently we have been applying our expertise on identifying and measuring weak interactions between the extracellular regions of leukocyte surface receptors to intracellular interactions. We have identified and measured SH3 and SH2 domain interactions between the cytoplasmic regions of leukocyte surface receptors at physiological temperature using proteins made in collaboration with the Oxford Protein Production Facility. One leukocyte surface receptor may interact with more than one extracellular or intracellular ligand thus it is important to establish a hierarchy as to which interaction is likely to occur in a given setting. We can then relate the quantitation of interactions to functional outcome in cellular experiments. I am focusing on leukocyte surface receptors in two families; the CD2 family with an emphasis on CD2 and 2B4 (CD244), and CD5 and CD6. CD2 and 2B4 contain related immunoglobulin superfamily domains in their extracellular regions but have different signalling mechanisms. CD2 contains proline rich motifs and 2B4 contains tyrosine motifs which bind the SH2 domain adaptor, SAP. CD5 and CD6 contain a different type of domain in their extracellular regions, the scavenger cysteine rich domain and both signal through tyrosine motifs. CD5 and CD6 are primarily T cell surface receptors, CD2 is expressed on T and NK cells whereas 2B4 is more predominantly an NK cell surface receptor. |
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Recent Publications |
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Foster-Cuevas M., Westerholt
T., Ahmed M., Brown M.H., Barclay A.N. and Voigt S. Cytomegalovirus e127
protein interacts with the inhibitory CD200 receptor. 2011. J Virol. 85:6055-6059. Mihrshahi, R. and M. H. Brown. 2010. Dok1 and Dok2
play opposing roles in CD200R signaling. J. Immunol.
185:7216-22. Brown, M. H., and E. Lacey. 2010. A Ligand for CD5 is CD5. J. Immunol. 185: 6068-6074. Mihrshahi, R., A.N.
Barclay and M. H. Brown. 2009.
Essential Roles for Dok2 and RasGAP in
CD200Receptor-Mediated Regulation of Human Myeloid Cells. J. Immunol. 183:4879-86. Clarkson, N.G., and
M.H. Brown. 2009. Inhibition and Activation by CD244 Depends on CD2 and
Phospholipase C- Garza-Garcia, A., D. Esposito, W. Rieping, R. Harris, C. Briggs, M.H. Brown, and P.C.
Driscoll. 2008. Three-dimensional solution structure and conformational
plasticity of the N-terminal scavenger receptor cysteine-rich domain of human
CD5. Clarkson, N.G., S.J. Simmonds, M.J. Puklavec,
and M.H. Brown. 2007. Direct and Indirect Interactions of the Cytoplasmic
Region of CD244 (2B4) in Mice and Humans with Hassan, N.J., S.J.
Simmonds, N.G. Clarkson, S. Hanrahan, M.J. Puklavec, M. Bomb, A.N. Barclay, and M.H. Brown. 2006.
CD6 Regulates T-Cell Responses through Activation-Dependent Recruitment of
the Positive Regulator SLP-76. Mol Cell Biol 26:6727-6738. Barclay AN, Brown MH.
The SIRP family of receptors and immune regulation. Voulgaraki,
D., R. Mitnacht-Kraus, M. Letarte,
M. Foster-Cuevas, M. H. Brown, and A. N. Barclay. 2005. Multivalent
recombinant proteins for probing functions of leucocyte surface proteins such
as the CD200 receptor. Immunology
115:337-46 Foster-Cuevas, M., G. J. Wright, M. J. Puklavec,
and A. N. Barclay. 2004. Human Herpesvirus-8 K14 protein mimics CD200 in
down-regulating macrophage activation through CD200 receptor. J
Virol. 78:7667-76. Brooke G, J.D. Holbrook, M.H. Brown, A.N. Barclay. 2004. Human
lymphocytes interact directly with CD47 through a novel member of the signal
regulatory protein (SIRP) family. J
Immunol
173: 2562-70
Hanna, S. M., P. Kirk, O. J. Holt, M. J. Puklavec, M. H. Brown, and A. N. Barclay. 2003. A novel form of the membrane protein CD147 that contains an extra Ig-like domain and interacts homophilically. BMC Biochem 4:17. Hutchings, N. J., N. Clarkson, R. Chalkley,
A. N. Barclay, and M. H. Brown. 2003. Linking the T cell surface protein CD2
to the actin-capping protein CAPZ via CMS and CIN85. J.
Biol. Chem. 278:22396-403. |
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Email Addresses of Group Members |
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3 February 2006 |