CONTACT INFORMATION http://www.loyola.org
Tarun Patel
Ph.D.
  • Professor
  • Molecular Pharmacology and Therapeutics
Research Summary

Signaling mechanisms in cancer and cardiovascular diseases

Receptor tyrosine kinases are involved in the regulation of numerous biological processes such as organogenesis, angiogenesis, cardiovascular function and neuroplasticity. Receptor tyrosine kinases also play a significant role in the etiology and progression of pathological conditions and are overexpressed in certain forms of cancers and augment metastasis and progression of the disease. The activation of the downstream signaling elements of receptor tyrosine kinases also lead to cardiovascular pathologies such as cardiac hypertrophy. Hence, some of these kinases and their downstream signaling proteins are targets for development of newer drugs. Indeed, several inhibitors of receptor tyrosine kinases are either in clinical trial or being used to treat patients.

The overall goal of my research group is to understand the regulation of signaling processes that emanate from receptor tyrosine kinases with a special emphasis on identifying the molecular mechanisms involved. In this context, one of the projects in my laboratory concerns identifying the mechanisms by which Sprouty proteins modulate the biological actions of receptor tyrosine kinases.

Among the four members of the Sprouty family our research has focused mainly on the Sprouty2 protein. This protein is a potent inhibitor of growth factor- induced cell proliferation and migration. Our studies have shown that Sprouty2 mediates its anti-migratory actions, in part, by elevating the cytosolic amount and activity of protein tyrosine phosphatase 1B (PTP1B). On the other hand, the antiproliferative actions of Sprouty2 require the tumor suppressor protein PTEN. Sprouty2 increases the amount and activity of PTEN to inhibit cell proliferation. Moreover, by binding c-Cbl, Sprouty2 enhances cell survival. Currently, we are investigating the mechanisms by which Sprouty2 increases PTEN amount and activity as well as addressing how Sprouty2 increases the amount of cytosolic PTP1B.

The other project in our laboratory emanates from our long- tanding interest in regulation of adenylyl cyclases and cAMP- dependent protein kinase (protein kinase A; PKA). Recently, we demonstrated a novel interaction between the subunits of PKA and the immediate downstream kinase of ERK1/2, p90RSK1. This latter protein kinase plays an important role in augmenting cell survival as well as increasing protein synthesis. Essentially, we showed that the inactive RSK1 interacts with the regulatory subunit of PKA whilst the active RSK1 interacts with the catalytic subunit of PKA. The binding of RSK1 to the catalytic subunit of PKA increases the interactions between the catalytic and regulatory subunit of PKA with a resultant inhibition of PKA activity. On the other hand, by binding to the PKA subunits, the active RSK1 is localized to the nucleus. Disruption of the interactions of RSK1 with PKA subunits increases the amount of RSK1 in the cytoplasm, augments phosphorylation of its substrates such as the apoptotic protein BAD and increases the anti-apoptotic actions of growth factors such as EGF. Presently, we are elucidating the precise mechanisms by which the p90RSK1 and PKA subunits interact with each other and also unraveling the other biological functions of these interactions.

Publications

New Modalities for the Evaluation and Surveillance of Complex Renal CystsEllimoottil,C.; Greco,K. A.; Hart,S.; Patel,T.; Sheikh,M. M.; Turk,T. M.; Flanigan,R. C.The Journal of urology 2014 ; ( ):

TACC3 deregulates the DNA damage response and confers sensitivity to radiation and PARP inhibitionHa,G. H.; Kim,J. L.; Petersson,A.; Oh,S.; Denning,M. F.; Patel,T.; Breuer,E. K.Oncogene 2014( ):10.1038/onc.2014.105

Interactions between the Regulatory Subunit of Type I Protein Kinase A (PKARIalpha) and p90 Ribosomal S6 Kinase1 (RSK1) Regulate Cardiomyocyte ApoptosisGao,X.; Lin,B.; Sadayappan,S.; Patel,T. B.Molecular pharmacology 2013 ; ( ):

Localization and retention of p90 ribosomal S6 kinase 1 in the nucleus: implications for its functionGao,X.; Chaturvedi,D.; Patel,T. B.Molecular biology of the cell 2012 ;23(3):503-515

Sprouty2 downregulates angiogenesis during mouse skin wound healingWietecha,M. S.; Chen,L.; Ranzer,M. J.; Anderson,K.; Ying,C.; Patel,T. B.; DiPietro,L. A.American journal of physiology.Heart and circulatory physiology 2011 ;300(2):H459-67

Regulation of cellular levels of Sprouty2 protein by prolyl hydroxylase domain and von Hippel-Lindau proteinsAnderson,K.; Nordquist,K. A.; Gao,X.; Hicks,K. C.; Zhai,B.; Gygi,S. P.; Patel,T. B.The Journal of biological chemistry 2011 ;286(49):42027-42036

HECT domain-containing E3 ubiquitin ligase Nedd4 interacts with and ubiquitinates Sprouty2.Edwin,F.; Anderson,K.; Patel,T. B.Journal of Biological Chemistry 2010 ;285(1):255-264

p90 ribosomal S6 kinase 1 (RSK1) and the catalytic subunit of protein kinase A (PKA) compete for binding the pseudosubstrate region of PKAR1alpha: role in the regulation of PKA and RSK1 activities.Gao,X.; Chaturvedi,D.; Patel,T. B.Journal of Biological Chemistry 2010 ;285(10):6970-6979

Regulation of protein kinase A activity by p90 ribosomal S6 kinase 1.Gao,X.; Patel,T. B.Journal of Biological Chemistry 2009 ;284(48):33070-33078

Intermolecular interactions of Sprouty proteins and their implications in development and diseaseEdwin,F.; Anderson,K.; Ying,C.; Patel,T. B.Molecular pharmacology 2009 ;76(4):679-691

Route of epoetin administration influences hemoglobin variability in hemodialysis patients.Patel,T.; Hirter,A.; Kaufman,J.; Keithi-Reddy,S. R.; Reda,D.; Singh,A.American Journal of Nephrology 2009 ;29(6):532-537

Rifaximin Redux: treatment of recurrent Clostridium difficile infections with rifaximin immediately post-vancomycin treatment.Johnson,S.; Schriever,C.; Patel,U.; Patel,T.; Hecht,D. W.; Gerding,D. N.Anaerobe 2009 ;15(6):290-291

The PKARIalpha subunit of protein kinase A modulates the activation of p90RSK1 and its function.Chaturvedi,D.; Cohen,M. S.; Taunton,J.; Patel,T. B.Journal of Biological Chemistry 2009 ;284(35):23670-23681

Rapamycin induces transactivation of the EGFR and increases cell survival.Chaturvedi,D.; Gao,X.; Cohen,M. S.; Taunton,J.; Patel,T. B.Oncogene 2009 ;28(9):1187-1196

Transglutaminase-catalyzed transamidation: a novel mechanism for Rac1 activation by 5-hydroxytryptamine2A receptor stimulation.Dai,Y.; Dudek,N. L.; Patel,T. B.; Muma,N. A.Journal of Pharmacology & Experimental Therapeutics 2008 ;326(1):153-162

A novel role of Sprouty 2 in regulating cellular apoptosis.Edwin,F.; Patel,T. B.Journal of Biological Chemistry 2008 ;283(6):3181-3190

Electroconvulsive seizures stimulate glial proliferation and reduce expression of Sprouty2 within the prefrontal cortex of rats.Ongur,D.; Pohlman,J.; Dow,A. L.; Eisch,A. J.; Edwin,F.; Heckers,S.; Cohen,B. M.; Patel,T. B.; Carlezon,W. A.,JrBiological psychiatry 2007 ;62(5):505-512

Conditional stimulation of type V and VI adenylyl cyclases by G protein betagamma subunits.Gao,X.; Sadana,R.; Dessauer,C. W.; Patel,T. B.Journal of Biological Chemistry 2007 ;282(1):294-302

The tumor suppressor PTEN is necessary for human Sprouty 2-mediated inhibition of cell proliferation.Edwin,F.; Singh,R.; Endersby,R.; Baker,S. J.; Patel,T. B.Journal of Biological Chemistry 2006 ;281(8):4816-4822

A historical perspective of the EGF receptor and related systemsEdwin,F.; Wiepz,G. J.; Singh,R.; Peet,C. R.; Chaturvedi,D.; Bertics,P. J.; Patel,T. B.Methods in Molecular Biology 2006 ;327( ):1-24

Analysis of EGF receptor interactions with the alpha subunit of the stimulatory GTP binding protein of adenylyl cyclase, Gs.Chaturvedi,D.; Edwin,F.; Sun,H.; Patel,T. B.Methods in Molecular Biology 2006 ;327( ):49-59

Subcellular localization and biological actions of activated RSK1 are determined by its interactions with subunits of cyclic AMP-dependent protein kinase.Chaturvedi,D.; Poppleton,H. M.; Stringfield,T.; Barbier,A.; Patel,T. B.Molecular & Cellular Biology 2006 ;26(12):4586-4600

A recombinant transductor-effector system: in vitro study of G inhibitory protein (G-alpha-i1) direct activators.Di Cesare Mannelli,L.; Pacini,A.; Toscano,A.; Ghelardini,C.; Manetti,D.; Gualtieri,F.; Patel,T. B.; Bartolini,A.Archives of Biochemistry & Biophysics 2006 ;453(2):151-160

Methods for determining the proliferation of cells in response to EGFR ligands.Wiepz,G. J.; Edwin,F.; Patel,T.; Bertics,P. J.Methods in Molecular Biology 2006 ;327( ):179-187

Copper and zinc inhibit Galphas function: a nucleotide-free state of Galphas induced by Cu2+ and Zn2+.Gao,X.; Du,Z.; Patel,T. B.Journal of Biological Chemistry 2005 ;280(4):2579-2586

Histidine residues 912 and 913 in protein associated with Myc are necessary for the inhibition of adenylyl cyclase activity.Gao,X.; Patel,T. B.Molecular pharmacology 2005 ;67(1):42-49

Regulation of vascular smooth muscle cell proliferation and migration by human sprouty 2.Zhang,C.; Chaturvedi,D.; Jaggar,L.; Magnuson,D.; Lee,J. M.; Patel,T. B.Arteriosclerosis, Thrombosis & Vascular Biology 2005 ;25(3):533-538

The tumour necrosis factor-alpha inhibitor adalimumab rapidly reverses the decrease in epidermal Langerhans cell density in psoriatic plaques.Gordon,K. B.; Bonish,B. K.; Patel,T.; Leonardi,C. L.; Nickoloff,B. J.British Journal of Dermatology 2005 ;153(5):945-953

Optimal lysophosphatidic acid-induced DNA synthesis and cell migration but not survival require intact autophosphorylation sites of the epidermal growth factor receptorDeng,W.; Poppleton,H.; Yasuda,S.; Makarova,N.; Shinozuka,Y.; Wang,D. A.; Johnson,L. R.; Patel,T. B.; Tigyi,G.The Journal of biological chemistry 2004 ;279(46):47871-47880

Sprouty regulates cell migration by inhibiting the activation of Rac1 GTPase.Poppleton,H. M.; Edwin,F.; Jaggar,L.; Ray,R.; Johnson,L. R.; Patel,T. B.Biochemical & Biophysical Research Communications 2004 ;323(1):98-103

Adalimumab: efficacy and safety in psoriasis and rheumatoid arthritisPatel,T.; Gordon,K. B.Dermatologic Therapy 2004 ;17(5):427-431

Single transmembrane spanning heterotrimeric g protein-coupled receptors and their signaling cascadesPatel,T. B.Pharmacological reviews 2004 ;56(3):371-385

Protein-tyrosine phosphatase-1B (PTP1B) mediates the anti-migratory actions of SproutyYigzaw,Y.; Poppleton,H. M.; Sreejayan,N.; Hassid,A.; Patel,T. B.The Journal of biological chemistry 2003 ;278(1):284-288

Albumin: a Galpha(s)-specific guanine nucleotide dissociation inhibitor and GTPase activating proteinDu,Z.; Patel,T. B.ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS 2003 ;415(2):221-228

Functional analyses of type V adenylyl cyclasePatel,T. B.; Wittpoth,C.; Barbier,A. J.; Yigzaw,Y.; Scholich,K.Methods in enzymology 2002 ;345( ):160-187

Developmental expression of PAM (protein associated with MYC) in the rodent brainYang,H.; Scholich,K.; Poser,S.; Storm,D. R.; Patel,T. B.; Goldowitz,D.Brain Research.Developmental Brain Research 2002 ;136(1):35-42