Cell adhesion and migration are integral in a spectrum of biological processes including fertilization, embryonic development, wound healing, cancer metastasis, and immune function. With respect to immunity, immune cells maintain constant surveillance of the body by recirculating through the blood and lymphatic networks. Upon detection of a biological stimulus, immune cells will directionally emigrate to defined sites. The ability of immune cells to properly recirculate during immune surveillance and mount an effective immune response is dependent upon coordinated adhesion and migration. Specifically, our lab is interested in the role of ADAM (adisintegrin and metalloprotease) proteins in immune cell trafficking. ADAMs are cell surface and soluble glycoproteins uniquely exhibiting both adhesive and proteolytic properties. Catalytically active ADAMs are well-established ectodomain sheddases capable of transforming latent cell-bound substrates to soluble, biologically active derivatives. ADAM proteases play a crucial role in cell adhesion and migration through “shedding” cell surface proteins such as cytokines and growth factors. The disintegrin-like domains of ADAMs exhibit homology with small, nonenzymatic peptides contained in snake venom. Snake venom disintegrins disrupt platelet aggregation by acting as high affinity integrin receptor antagonists, thereby allowing broad diffusion of venom throughout the bite-victim, which greatly increases venom efficacy and toxicity. Homology with known integrin ligands and the biological significance of integrin receptors prompted studies of mammalian ADAM-integrin associations, and ADAMs are now recognized as a novel class of integrin ligand.
Novel regulatory mechanisms of the ADAM protease family
Despite a wealth of information regarding the ADAM family, the mechanism(s) of how ADAM enzymatic activity is controlled in biological settings remains unclear. We are interested in how ADAM proteolytic function is naturally regulated. Current models posit ADAM sheddase activity and specificity are governed by the molecular interaction of the nonproteolytic domains (e.g. integrin recognition of the disintegrin domain); however, the putative interplay between ADAM adhesive and proteolytic domains is poorly understood. Our lab is investigating factors/conditions (e.g. integrin expression, nutraceutical exposure) that modulate ADAM catalytic function to provide insight into how ADAMs contribute to human health and disease. ADAM dysregulation has been implicated in chronic inflammation, tumor establishment and metastasis, and Alzheimer’s.
Metabolic regulation of lymphocyte metalloprotease mediated shedding
Our lab has become increasingly interested in the contribution of metabolism in modulating ADAM function in the context of immunity. The necessity of Vitamin A for the proper establishment and maintenance of immunity has long been appreciated, but the precise role of Vitamin A in immunity has only begun to be elucidated within the past decade. We have recently demonstrated that Vitamin A oxidative metabolites stimulate immune cell adhesion to select ADAMs through two functionally distinct mechanisms. We are currently investigating how exposure to these metabolites translates into cell adhesion with respect to signal transduction and adhesion receptor expression. In addition, we are actively exploring the impact of other immune-modulating dietary factors (e.g. Vitamin D) on ADAM function.
Whelan JT, Chen J, Miller J, Morrow RL, Lingo JD, Merrell K, Shaikh SR, Bridges LC. 9-cis-Retinoic acid promotes cell adhesion through integrin dependent and independent mechanisms across immune lineages. J Nutr Biochem, in press. 2012.
Wei S, Xu G, Bridges LC, Williams P, Nakayama T, Shah A, Grainger RM, White JM, DeSimone DW. Roles of ADAM13-regulated Wnt activity in early Xenopus eye development. Dev Biol. 2012;363(1):147-154.
Wei S, Xu G, Bridges LC, Williams P, White JM, DeSimone DW. ADAM13 induces cranial neural crest by cleaving class B Ephrins and regulating Wnt signaling. Dev Cell. 2010;19(2):345-352.
Wei S, Whittaker CA, Xu G, Bridges LC, Shah A, White JM, Desimone DW. Conservation and divergence of ADAM family proteins in the Xenopus genome. BMC Evol Biol. 2010;10:211.
Bridges LC, Lingo JD, Grandon RA, Kelley MD. All-trans-retinoic acid induces integrin-independent B-cell adhesion to ADAM disintegrin domains. Biochemistry. 2008;47(15):4544-4551.
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