My laboratory has two major focuses. The first is centred on defining signalling pathways regulating smooth (SM) and striated muscle (SKM) contractility and plasticity. The second focuses on using novel chemoproteomic technology to define chemical starting points for drug discovery to treat diseases of the developing world. Both areas of interest adopt a multidisciplinary approach combining the strengths of cutting edge technologies such as mass spectrometry and chemoproteomics with classical approaches such as physiological studies in isolated tissues, mouse genetics and biochemical methods. In our SM/SKM work we utilized a combination of proteomics and muscle physiology to identify ZIPK as a major regulator of Ca2+ independent regulation of smooth muscle contraction. We now believe that ZIPK may be an exquisite drug target for the development of a new generation of antihypertensive drugs. We also utilized proteomics to define early phosphorylation events in response to activation of PKA and PKG in SM. Several novel phosphoprotein targets were identified, including SMTNL1. SMTNL1 shows discrete expression that confines the protein to certain SM and to type IIa fibres in SKM. Studies with the SMTNL1 null mouse shows that the protein plays a critical role in adaptive responses to exercise and pregnancy. SMTNL1 null male mice appear to be already exercised adapted, particularly with respect to their cardiovascular responses. Additionally, in female mice, SMTNL1 deletion mimics pregnancy induced phenotypic changes in both SM and SKM. These findings suggest that both cAMP/cGMP as well as steroid hormone receptor mediated signalling pathways contribute in previously unrecognized ways to SM and SKM adaptive responses. Our drug discovery program in infectious diseases utilizes proteome mining technology to define novel chemical starting points for multiple diseases affecting the developing world including Malaria, Leishmania, opportunistic fungal infections as well as viral infections such as Dengue fever and Yellow fever, HIV-1 and influenza. Some of this work is funded at Duke, but more is anticipated to be supported by a novel Duke spin out, not for profit organization, The Institute for Global Disease Medicines (www.instgdm.com).

Alms GR, Sanz P, Carlson M and Haystead TAJ. (1999) Reg1p targets protein phosphatase 1 to dephosphorylate hexokinase II in Saccharomyces cerevisiae: Characterizing the effects of a phosphatase subunit on the yeast proteome. EMBO J.18 (15):4157-4168.

MacDonald JM, Borman MA, Murányi A, Hartshorne DJ and Haystead TAJ.(2001) Identification of a myosin phosphatase associated kinase regulated by the Rho-kinase pathway. PNAS (98) 2419-2424.

MacDonald, J.A., Eto,M., Borman, M.A., Brautigan,M., and Haystead, T.A.J. (2001). Dual Ser and Thr phosphorylation of CPI-17, an inhibitor of myosin phosphatase, by MYPT-associated kinase. FEBS Lett. 493 (2-3):91-4.

Graves PR, Haystead TA. Molecular biologist's guide to proteomics. Microbiol Mol Biol Rev. 2002 Mar;66(1):39-63; table of contents. Review.

MacDonald JA, Mackey AJ, Pearson WR, Haystead TA. A strategy for the rapid identification of phosphorylation sites in the phosphoproteome. Mol Cell Proteomics. 2002 Apr;1(4):314-22.

Borman MA, MacDonald JA, Muranyi A, Hartshorne DJ, Haystead TA. Smooth muscle myosin phosphatase-associated kinase induces Ca2+ sensitization via myosin phosphatase inhibition. J Biol Chem. 2002 Jun 28;277(26):23441-6.

Graves PR, Kwiek JJ, Fadden P, Ray R, Hardeman K, Coley AM, Foley M, and Haystead TA. Discovery of Novel Targets of Quinoline Drugs in the Human Purine Binding Proteome. Mol Pharmacol December 2002 Dec;62(6):1364-72

Kwiek JJ, Haystead TA, Rudolph J. Kinetic mechanism of quinone oxidoreductase 2 and its inhibition by the antimalarial quinolines.Biochemistry. 2004 Apr 20;43(15):4538-47.

Wooldridge AA, MacDonald JA, Erdodi F, Ma C, Borman MA, Hartshorne DJ, Haystead TA. Smooth muscle phosphatase is regulated in vivo by exclusion of phosphorylation of Threonine 696 of MYPT1 by phosphorylation of Serine 695 in response to cyclic nucleotides. J Biol Chem. 2004 Aug 13;279(33):34496-504.

Graves PR, Winkfield KM, Haystead TA. Regulation of ZIP kinase activity in vitro and in vivo by multi-site phosphorylation.J Biol Chem. 2005 Mar 11;280(10):9363-74.

Kwiek NC, Thacker DF, Datto MB, Megosh HB, Haystead TA. PITK, a PP1 targeting subunit that modulates the phosphorylation of the transcriptional regulator hnRNP K. Cell Signal. 2006 Oct;18(10):1769-78.

Hagerty L, Weitzel DH, Chambers J, Fortner CN, Brush MH, Loiselle D, Hosoya H, Haystead TA. ROCK1 phosphorylates and activates ZIP kinase. J Biol Chem. 2007 Feb 16;282(7):4884-93.

Philip N, Haystead TA. Characterization of a UBC13 kinase in Plasmodium falciparum Proc Natl Acad Sci U S A. 2007 May 8;104(19):7845-50

Wooldridge AA, Fortner CN, Lontay B, Akimoto T, Neppl RL, Facemire C, Datto MB, Kwon A, McCook E, Li P, Wang S, Thresher RJ, Miller SE, Perriard JC, Gavin TP, Hickner RC, Coffman TM, Somlyo AV, Yan Z, Haystead TA. Deletion of the PKA/PKG target SMTNL1 promotes an exercise-adapted phenotype in vascular smooth muscle. J Biol Chem. 2008 Apr 25;283(17):11850-9.