Michael Holinstat, Ph.D.

Contact Dr. Holinstat

1015 Walnut Street
Suite 320
Philadelphia, PA 19107

(215) 955-6121
(215) 955-9170 fax

Research and Clinical Interests
My lab focuses on understanding the complex signaling underlying small GTPases that regulate normal vascular hemostasis. Small G proteins are composed of one subunit (alpha) which is continuously cycling between an inactive (GDP) and active (GTP) form. In the active form, small G proteins regulate a number of physiologically crucial processes. Specifically, we are interested in how Rap1, a small G protein central to activation of integrins in platelets, is regulated through the various receptor activation pathways. Since activation of all of these pathways eventually lead to activation of Rap1, elucidating the mechanisms by which Rap1 is activated, inactivated and propagates its signal may allow for the development of novel anti-platelet therapies for the treatment of thrombosis leading to vessel occlusion and stroke.

Rap1 function in cardiovascular disease.
Cardiovascular disease (CVD) is the leading cause of death globally and nearly 50% of men and 35% of women will be diagnosed with a cardiovascular disease by age 40. CVD and Diabetes lead to a shift in the threshold for platelet activation. Currently, it is unclear what the mechanisms regulating this shift toward a pro-thrombotic state are. We are investigating how the progression of these vascular disorders may alter the signaling of Rap1 as well as other small G proteins that regulate platelet function. Identifying where these signaling modifications are taking place will allow for better treatment of people suffering from these and possibly other related vascular disorders such as edema and DVT.

Publications

Most recent Peer-reviewed Publications

Irreversible platelet activation requires protease-activated receptor 1-mediated signaling to phosphatidylinositol phosphates. Holinstat M, Preininger AM, Milne SB, Hudson WJ, Brown HA, Hamm HE. Mol Pharmacol. 2009 Aug;76(2):301-13. Epub 2009 May 29.

PAR1, but not PAR4, activates human platelets through a Gi/o/phosphoinositide-3 kinase signaling axis. Voss B, McLaughlin JN, Holinstat M, Zent R, Hamm HE. Mol Pharmacol. 2007 May;71(5):1399-406. Epub 2007 Feb 15.

Protease-activated receptors differentially regulate human platelet activation through a phosphatidic acid-dependent pathway. Holinstat M, Voss B, Bilodeau ML, Hamm HE.

Mol Pharmacol. 2007 Mar;71(3):686-94. Epub 2006 Dec 6. Erratum in: Mol Pharmacol. 2009 Mar;75(3):730-1.

G-protein-coupled receptors: evolving views on physiological signalling: symposium on G-protein-coupled receptors: evolving concepts and new techniques. Holinstat M, Oldham WM, Hamm HE. EMBO Rep. 2006 Sep;7(9):866-9. Epub 2006 Aug 11. No abstract available.

PAR4, but not PAR1, signals human platelet aggregation via Ca2+ mobilization and synergistic P2Y12 receptor activation. Holinstat M, Voss B, Bilodeau ML, McLaughlin JN, Cleator J, Hamm HE. J Biol Chem. 2006 Sep 8;281(36):26665-74. Epub 2006 Jul 12.

Suppression of RhoA activity by focal adhesion kinase-induced activation of p190RhoGAP: role in regulation of endothelial permeability. Holinstat M, Knezevic N, Broman M, Samarel AM, Malik AB, Mehta D. J Biol Chem. 2006 Jan 27;281(4):2296-305. Epub 2005 Nov 24.

Functional selectivity of G protein signaling by agonist peptides and thrombin for the protease-activated receptor-1. McLaughlin JN, Shen L, Holinstat M, Brooks JD, Dibenedetto E, Hamm HE. J Biol Chem. 2005 Jul 1;280(26):25048-59. Epub 2005 May 4.

Interaural level difference processing in the lateral superior olive and the inferior colliculus. Park TJ, Klug A, Holinstat M, Grothe B. J Neurophysiol. 2004 Jul;92(1):289-301. Epub 2004 Mar 31.

Protein kinase Calpha phosphorylates the TRPC1 channel and regulates store-operated Ca2+ entry in endothelial cells. Ahmmed GU, Mehta D, Vogel S, Holinstat M, Paria BC, Tiruppathi C, Malik AB. J Biol Chem. 2004 May 14;279(20):20941-9. Epub 2004 Mar 10.

RhoA interaction with inositol 1,4,5-trisphosphate receptor and transient receptor potential channel-1 regulates Ca2+ entry. Role in signaling increased endothelial permeability. Mehta D, Ahmmed GU, Paria BC, Holinstat M, Voyno-Yasenetskaya T, Tiruppathi C, Minshall RD, Malik AB. J Biol Chem. 2003 Aug 29;278(35):33492-500. Epub 2003 May 22.

Protein kinase Calpha-induced p115RhoGEF phosphorylation signals endothelial cytoskeletal rearrangement. Holinstat M, Mehta D, Kozasa T, Minshall RD, Malik AB.J Biol Chem. 2003 Aug 1;278(31):28793-8. Epub 2003 May 16.

Modulatory role of focal adhesion kinase in regulating human pulmonary arterial endothelial barrier function. Mehta D, Tiruppathi C, Sandoval R, Minshall RD, Holinstat M, Malik AB. J Physiol. 2002 Mar 15;539(Pt 3):779-89.