Dr Susanna Fagerholm

Research

Regulation of Integrin-Mediated Leukocyte Adhesion And Migration

Leukocyte beta2-integrins are heterodimeric adhesion and signalling receptors. They are key players in both innate and adaptive immune responses. Integrins are also recognized therapeutic targets for intervention with human disease. Recently, monoclonal antibodies against integrin extracellular domains have shown success in the treatment of psoriasis, inflammatory bowel disease and multiple sclerosis in humans, demonstrating the considerable potential of antiadhesion therapy directed at leukocyte integrins.
The importance of beta2-integrins, LFA-1 (alphaLbeta2 or CD11a/CD18) and Mac-1 (alphaMbeta2, CD11b/CD18) (and the other two members of this family) is demonstrated by the rare genetic disorder leukocyte adhesion deficiency-I (LAD-I), in which beta2-integrin expression or function is diminished or lost. Patients with this disease suffer from recurrent bacterial infections, and in severe cases, death will occur in early childhood unless bone marrow transplants are performed. Beta2-integrin deficient leukocytes fail to exit the blood stream to the sites of infections to clear pathogens, as the interactions with the endothelium surrounding the blood vessels are largely inhibited. Beta2-integrins are also important for leukocyte signalling and effector functions.

In light of these diverse roles of integrins in regulating leukocyte biology, it is important to understand the role and regulation of beta2-integrins in leukocytes, so as to be able to understand the clinical implications of therapeutic interventions in beta2-integrin function. Additionally, research in this area can be useful in the development of novel therapeutics for inflammatory disorders, autoimmune disease and cancer.

Beta2-integrin binding to ligands occurs only after the cell has received an activating stimulus, such as stimulation of the T cell receptor (TCR), chemokine receptors or other cell surface receptors. After intracellular signalling events initiated by these receptors, activation of integrins is achieved by the binding of cytoplasmic factors to the integrin intracellular domains (tails). To achieve integrin activation only when it is needed, the interactions between integrin cytoplasmic domains and intracellular activating factors have to be strictly controlled. One way of regulating these interactions is by direct phosphorylation of the integrin tails. Work in my laboratory in concentrating on the phosphorylation of integrin tails and the role of these phosphorylations in regulating different integrin functions, such as adhesion, cell spreading, signalling and migration, as well as in vivo roles in the regulation of the immune system. We are also interested in signaling pathways that regulate leukocyte integrins, and other signaling events that regulate adhesion and migration in the immune system.

Publications

1. Takala H, Nurminen E, Nurmi SM, Aatonen M, Strandin T, Takatalo M, Kiema T, Gahmberg CG, Ylänne J, and Fagerholm SC. 2008. Integrin beta2 phosphorylation on Thr758 acts as a molecular switch to regulate 14-3-3 and filamin binding. Blood, 112(5):1853-62.
2. Nurmi, S.M., Autero, M., Raunio, A., Gahmberg, C. G. and Fagerholm S. C. 2007. Phosphorylation of the LFA-1 integrin beta2-chain on Thr758 leads to adhesion, Rac-1/Cdc42 activation and stimulation of CD69 expression in human T cells. J. Biol. Chem, 282:968-75.
3. Fagerholm, S. C., Varis, M., Stefanidakis, M., Hilden T. J. and Gahmberg, C. G. 2006. alpha-chain phosphorylation of the human leukocyte CD11b/CD18 (Mac-1) integrin is pivotal for integrin activation to bind ICAMs and leukocyte extravasation in vivo. Blood. 108: 3379-3386.
4. Hilden, T. J., Nurmi, S., Fagerholm, S. C. and Gahmberg, C. G. 2006. Interfering with leukocyte integrin activation: a novel concept in the development of anti-inflammatory drugs. Ann Med. 38: 503-511
5. Fagerholm, S.C., Hilden, T., Nurmi, S. and Gahmberg, C. G. 2005. Specific integrin alpha and beta chain phosphorylations regulate LFA-1 activation through affinity-dependent and independent mechanisms. J. Cell Biol. 171: 705-715.
6. Fagerholm, S.C., Hilden T. and Gahmberg, C. G. 2004. P marks the spot – site-specific integrin phosphorylation regulates molecular interactions. Trends Biochem Sci. 29: 504-512.
7. Fagerholm, S., Morrice, N., Gahmberg, C. G. and Cohen, P. 2002. Phosphorylation of the cytoplasmic domain of the integrin CD18 chain by protein kinase C isoforms in leukocytes. J. Biol. Chem. 277: 1728-1738.

Funding

Cancer Research UK, Tenovus Scotland, the Anonymous Trust, the Magnus Ehrnrooth Foundation, BBSRC.

Lab members:

Dr Matthew MacPherson, Postdoctoral Research Assistant

Miss Hwee San Lek, Technician