 |
Raymond R. Mattingly, PhD
|
RESEARCH INTERESTS:
Cellular and Molecular Pharmacology:
Signal Transduction through Small GTPases of the Ras Superfamily
Background: Pathways of intracellular signal transduction are a principal characteristic of eukaryotic cells. Signals are relayed through a variety of components that include receptors for hormones and neurotransmitters, the timed molecular switches of the GTPase superfamily, low molecular weight second messengers, and the many protein kinases. Signalling is often directed to the nucleus and the control of transcription factors. Integration and feedback-regulation of signal transduction provides exquisite control of complex, differentiated cells. It is this control that underlies phenomena such as cell proliferation and programmed cell death (apoptosis) and executes processes that include memory and development. Derangement of signal transduction produces diseases such as cancer and diabetes.
Active Projects: Our studies focus on the physiological roles and pharmacological significance of small GTPases of the Ras superfamily. We are currently pursuing three related investigations:
1. We have discovered a new mechanism for Ras activation by an exchange factor called Ras-GRF1. Heterotrimeric G-protein beta/gamma-subunits and an increase in phosphorylation of Ras-GRF1 on serine residues mediate this pathway. Pharmacological studies indicate that this phosphorylation and activation are induced selectively by G protein-coupled receptors acting through a novel protein kinase activity.
2. Type 1 Neurofibromatosis (NF1) is a common genetic disorder that is characterized by abnormal proliferation of neuroectodermal tissues. Nearly all patients have benign neurofibromas, and there is increased risk of neurofibrosarcomas and other malignant tumours. Current therapy for this disease is limited. We have developed collaborative projects with the goal of the identification of relatively non-toxic and mechanistically specific drugs for NF1 treatment. Our hypothesis is that the interaction of Ras and growth factor receptors underlies the pathological development of NF1 and provides therapeutic targets.
3. Early stages of cancer exhibit hyperproliferation of epithelium coupled to increased survival of the epithelial cells without their normal attachments. The latter property is a suppression of the normal process of detachment-induced cell death, or anoikis. We are investigating the hypothesis that the Rac effector protein kinase termed PAK1 may play a key role in early breast carcinoma through its potential actions to co-ordinate cytoskeletal rearrangement, to increase intra- and peri-cellular proteolysis, and to suppress anoikis.
Lab Personnel
Quanwen Li, postdoctoral research associate
Jonathan Wojtkowiak, pharmacology graduate student
Komal Sane, pharmacology graduate student
Hitchintan Kaur, graduate student
Ryan Anderson, undergraduate student
Ray Menard, PhD 2003, now an Instructor at St Petersburg College
Huibin Yang, postdoctoral research associate (2002 – 5), now Research Investigator at the University of Michigan
Josh Dilworth, PhD 2006, now medical resident at Beaumont Hospital
Dan LaLonde, summer undergraduate student (2004 – 7), now in Wayne State University medical school
Selected Recent Publications
* H. Yang & R.R. Mattingly. The Ras-GRF1 exchange factor coordinates activation of H-Ras and Rac1 to control neuronal morphology. Mol. Biol. Cell 17: 2177-2189 (2006)
[http://www.ncbi.nlm.nih.gov/pubmed/16481401]
* M.K. Clark, S.A. Reigard, J. Wojtkowiak, R. Chirco, P. Mathieu, J.J. Reiners Jr, R.R. Mattingly, R.F. Borch & R.A. Gibbs. Synthesis, biochemical, and cellular evaluation of farnesyl monophosphate prodrugs as farnesyltransferase inhibitors. J. Med. Chem. 50: 3274-3282 (2007)
[http://www.ncbi.nlm.nih.gov/pubmed/17555307]
* D.R. Yingst, T.M. Doci, K. Massey, N.F. Rossi , E. Rucker & R.R. Mattingly. Angiotensin II Stimulates Elution of Na,K-ATPase from a Digoxin-affinity Column by Increasing the Kinetic Response to Ligands that Trigger the Decay of E2-P. Am. J. Physiol. Renal, 294: 990-1000 (2008)
[http://www.ncbi.nlm.nih.gov/pubmed/18272598]
* Q. Li, S. Roshy-Mullins, B.F. Sloane & R.R. Mattingly. p21-activated Kinase 1 Coordinates Aberrant Cell Survival and Pericellular Proteolysis in a Three-dimensional Culture Model for Pre-malignant Progression of Human Breast Cancer. Neoplasia 10: 314-328 (2008)
[http://www.ncbi.nlm.nih.gov/pubmed/18392133]
* J.W. Wojtkowiak, F. Fouad, D.T. LaLonde, R.A. Gibbs, J.J. Reiners Jr, R.F. Borch & R.R. Mattingly. Induction of apoptosis in Neurofibromatosis Type 1 malignant peripheral nerve sheath tumor cell lines by a combination of novel farnesyl transferase inhibitors and lovastatin. J. Pharmacol. Exp. Ther. In press, doi:10.1124/jpet.107.135830 (2008)
[http://www.ncbi.nlm.nih.gov/pubmed/18367665]
Search PubMed for publications from the Mattingly Lab
