T. Kendall Harden

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Research Interests

• Phospholipase C and inositol lipid signaling
• P2Y receptors for extracellular nucleotides
• G proteins

Research Synopsis

The physiological responses of many hormones, neurotransmitters, growth factors, and other extracellular stimuli are mediated through phospholipase C (PLC)-catalyzed hydrolysis of membrane phosphoinositides. A long-term goal of our research is to delineate the molecular mechanisms whereby PLC activity is modulated by receptor-activated heterotrimeric and Ras superfamily G proteins, as well as by tyrosine phosphorylation. This work currently focuses on three PLC isozymes: (1) PLC-β isozymes, which are the prototypical heterotrimeric G protein-regulated PLCs, (2) PLC-ε, which we discovered is uniquely directly activated by both Rho and Ras GTPases acting through independent domains; and (3) PLC-γ isozymes, which are activated by phosphorylation by receptor and non-receptor tyrosine kinases. These studies are carried out in collaboration with John Sondek and are increasingly driven by high-resolution crystal structures.

Our research also focuses on mechanistic and pharmacological aspects of a class of G protein-coupled receptors (the eight member P2Y receptor family) for extracellular nucleotides. Clopidogrel (Plavix), an important and highly prescribed antithrombotic agent, targets the P2Y12 receptor, and the potential for therapeutic intervention at this and the other seven P2Y receptors is very high. Therefore, one of the goals of our P2Y receptor research program is to synthesize and develop highly selective agonists and antagonists of each of the P2Y receptor subtypes in work carried out in collaboration with Ken Jacobson at the National Institute of Health. A collaboration with Eduardo Lazarowski in the Department of Medicine and Cystic Fibrosis Center at UNC focuses on delineation of the cell signaling mechanisms and biological responses downstream of the nucleotide sugar-activated P2Y14 receptor.

Publications

Click above for PubMed publications.

• Waldo, G.L., Ricks, T.K., Hicks, S.N., Cheever, M.L., Kawano, T., Tzuboi, K., Wang, X., Montell, C., Kozasa, T., Sondek, J. and Harden, T.K. (2010) Kinetic Scaffolding Mediated by a Phospholipase C-β and G_q Signaling Complex. Science 330: 974-980. Abstract
• Elliot MR, Chekeni FB, Lazarowski ER, Harden TK, Leitinger N, and Ravichandran KS. (2009) Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461:282-286. Abstract
• Carter RL, Fricks IP, Barrett MO, Burianek LE, Zhou Y, Ko H, Das A, Jacobson KA, Lazarowski ER, and Harden TK. (2009) Quantification of Gi-mediated inhibition of adenylyl cyclase activity reveals that UDP is a potent agonist of the human P2Y14 receptor. Mol. Pharmacol. 76:1341-1348. Abstract
• Harden TK, Hicks SN, and Sondek J. (2009) Phospholipase C isozymes as effectors of Ras superfamily GTPases. J Lipid Res. 50:S243-248. Abstract
• Seifert, J.P., Zhou, Y., Hicks, S.N., Sondek, J., and Harden, T.K. (2008) Dual activation of phospholipase C-ε by Rho and Ras GTPases. J Biol Chem 283: 29690-29698. Abstract
• Hicks, S.N., Jezyk, M., Seifert, J.P., Harden, T.K., and Sondek, J. (2008) General and versatile autoinhibition of phospholipase C isozymes. Mol Cell 31: 383-394. Abstract
• Zhou, Y., Sondek, J., and Harden, T.K. (2008) Activation of human phospholipase C-η2 by Gβγ. Biochemistry 47: 4410-4417. Abstract
• Cheever, M.L., Snyder, J.T., Gershburg, S., Siderovski, D.P., Harden, T.K., and Sondek, J. (2008) Crystal structure of the multifunctional Gβ5-RGS9 complex. Nature Struct Mol Biol 15: 155-162. Abstract

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