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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 focuses on three PLC isozymes: (1) PLC-β isozymes, which are the prototypical heterotrimeric G protein-regulated PLCs, (2) PLC-ε, which 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.

Our research also focuses on mechanistic and pharmacological aspects of a class of G protein-coupled receptors (the eight member P2Y receptor family) that are activated by extracellular nucleotides.

Publications

Click above for PubMed publications.

• Sesma JI, Kreda SM, Steinckwich-Besancon N, Dang H, Garcia-Mata R, Harden TK, and Lazarowski ER.  The UDP-sugar-sensing P2Y₁₄ receptor promotes Rho-mediated signaling and chemotaxis in human neutrophils.  Am. J. Physiol. Cell Physiol. 303:C490-498, 2012. Abstract

• Harden TK, Waldo GL, Hicks SN, and Sondek J.  Mechanism of activation and inactivation of Gq/phospholipase C-β signaling nodes.  Chemical Rev. 111:6120-6129, 2011. Abstract

• 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.  Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance.  Nature, 461:282-286, 2009. Abstract

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