The Role of FAK and Pyk2 in the Activation of Human T cells

Human T cells control the adaptive immune response to pathogens and are also linked to the pathogenesis of multiple human diseases. T cells require two stimulatory signals to become fully activated. The first of these signals is delivered after the TCR binds its cognate peptide: MHC complex, while the second signal can be achieved through ligation of one of many costimulatory receptors, such as VLA-4. Currently, our understanding of how the signaling pathways downstream of the TCR and VLA-4 converge to regulate T cell activation is not completely understood. A better understanding of proteins that regulate the activation of these pathways is important, since they may prove useful for the development of therapeutic targets to treat T cell-mediated immunological disorders.

Two intracellular non-receptor tyrosine kinases activated following both TCR and VLA-4 ligation are FAK and Pyk2. In other immune cells, Fak and Pyk2 have been shown to be involved in processes the regulate actin cytoskeleton reorganization and migration. However, their functions in TCR- and VLA-4-mediated signaling in human T cells have not been investigated. We have developed a microRNA silencing technique to study the functions of Fak and Pyk2 downstream of the TCR and VLA-4. Using this strategy along with quantitative biochemical and biophysical techniques, we aim to characterize the functions of Fak and Pyk2 as they relate to the TCR- and VLA-4-mediated activation of human T cells. These studies will identify novel functions for Fak and Pyk2 and will provide insight as to whether FAK and Pyk2 could serve as useful therapeutic targets in the treatment of a variety of immunologic diseases.

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Vacaflores A, Freedman SN, Chapman NM, Houtman JC. Pretreatment of activated human CD8 T cells with IL-12 leads to enhanced TCR-induced signaling and cytokine production. Mol Immunol. 2017 Jan;81:1-15. doi: 10.1016/j.molimm.2016.11.008. PubMed PMID: 27883938; PubMed Central PMCID: PMC5201458.

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Chapman NM, Houtman JC. Functions of the FAK family kinases in T cells: beyond actin cytoskeletal rearrangement. Immunol Res. 2014 May 11. [Epub ahead of print] PubMed PMID: 24816556; PubMed Central PMCID:PMC4125427.

Chapman NM, Connolly SF, Reinl EL, Houtman JC. Focal adhesion kinase negatively regulates Lck function downstream of the T cell antigen receptor. J Immunol. 2013 Dec 15;191(12):6208-21. doi: 10.4049/jimmunol.1301587. Epub 2013 Nov 13. PubMed PMID: 24227778; PubMed Central PMCID: PMC3865716.

Chapman NM, Yoder AN, Houtman JC. Non-catalytic functions of Pyk2 and Fyn regulate late stage adhesion in human T cells. PLoS One. 2012;7(12):e53011. doi: 10.1371/journal.pone.0053011. Epub 2012 Dec 27. PubMed PMID: 23300847; PubMed Central PMCID: PMC3531412.

Chapman NM, Bilal MY, Cruz-Orcutt N, Knudson C, Madinaveitia S, Light J, Houtman JC. Distinct signaling pathways regulate TLR2 co-stimulatory function in human T cells. Cell Signal. 2013 Mar;25(3):639-50. doi:10.1016/j.cellsig.2012.11.026. Epub 2012 Dec 5. PubMed PMID: 23219913; PubMed Central PMCID: PMC3883577.

Collins M, Tremblay M, Chapman N, Curtiss M, Rothman PB, Houtman JC. The T cell receptor-mediated phosphorylation of Pyk2 tyrosines 402 and 580 occurs via a distinct mechanism than other receptor systems. J Leukoc Biol. 2010 Apr;87(4):691-701. doi: 10.1189/jlb.0409227. Epub 2009 Dec 22. PubMed PMID:20028775.

Honors and Awards

• Student representative, Immunology Curriculum Committee
• Supported by the T32 Immunology Predoctoral Training Grant (August 2008-June 2011)
• American Heart Association Pre-doctoral Fellowship (July 2011-June 2013)
• Graduate Student Senate (GSS) Travel Funds award