Shah, Kavita - Purdue University - Department of Chemistry

个人简介

Ph.D. Indian Institute of Technology, Kanpur, India, 1991; Postdoctoral Fellow, UMDNJ-Robert wood Johnson Medical School, New Jersey, 1993-94; Postdoctoral Fellow Princeton University, 1994-99.

研究领域

Intracellular phosphorylation of target proteins by protein kinases acts as a chemical switch that allows the cell to transmit stimuli from the plasma membrane to the nucleus in a highly regulated manner. Identification of the direct substrates of protein kinases could lead to an understanding of the complex interplay between kinases and the activation and recruitment of downstream effector proteins. This goal has proven elusive to genetic methods because of the tremendous redundancy and overlapping substrate specificities among protein kinases. Similarly, it is enormously challenging to find highly specific inhibitors for kinases because of the conserved nature of kinase active sites. A chemical-genetic method has been developed recently to address this issue. Proteins involved in signal transduction most often bind small molecules as co-factors in well conserved binding pockets. In light of this fact, genetic engineering and chemistry can be brought together to design specific protein/ligand pairs. A functionally-silent mutation was introduced in the active site of a protein kinase to allow for the specific use of a labeled ATP analog. We have successfully applied this method to the study of several kinases, uncovering previously unknown substrates and relationships. These tools have allowed us to probe the roles of multiple kinases involved in cancer and neurodegenerative diseases. Another project in the laboratory is aimed towards developing specific activators and inhibitors of any G protein of interest. Involved in almost all aspects of cellular function, G proteins are a large family of proteins comprising approximately 0.5% of mammalian genomes. A wide variety of diseases have their roots in deregulated G protein activities or have harmful signals conveyed through them. Despite their great potential as drug targets, no active site inhibitors are known to date. Traditionally, the surprising affinity of G proteins for their substrates and the high intracellular concentration of GTP have been blamed for this failure. The lack of such tools to allow specific and temporal control over the activities of G proteins has significantly impeded the elucidation of their pathways. We used H-Ras to develop a system answering this need. Convergent engineering of the nucleotide and of its binding pocket resulted in the production of two complementary small molecule/mutant protein pairs leading to the highly specific inhibition or activation of this G protein. This system allows for the highly selective identification of effectors of G proteins to help elucidate their signaling pathways

近期论文

查看导师新发文章（温馨提示：请注意重名现象，建议点开原文通过作者单位确认）

Chang KH, Vincent F, Shah K. (2012) Deregulated Cdk5 Triggers Aberrant Activation of Cell Cycle Kinases and Phosphatases Inducing Neuronal Death. J Cell Science (In Press). Johnson EO, Chang KH, Ghosh S, Venkatesh C, Giger K, Low PS, Shah K. (2012) LIMK2 is a Crucial Regulator and Effector of Aurora A-Mediated Malignancy. J Cell Science 125 (Pt 5), 1204-16. Kumar D, Kumar NM, Ghosh S, Shah K. (2012) Novel bis(indolyl)hydrazide-hydrazones as potent anticancer agents. Bioorg Med Chem Lett. 22(1), 212-5. Kumar D, Kumar NM, Noel B, Shah K. (2012) A series of 2-arylamino-5-(indolyl)-1,3,4-thiadiazoles as potent cytotoxic agents. Eur J Med Chem. (In press). Johnson EO, Chang KH, de Pablo Y, Ghosh S, Mehta R, Badve S, Shah K. (2011) PHLDA1 is a Crucial Negative Regulator and Effector of Aurora A Kinase in Breast Cancer. J Cell Science 124, 2711-2722. Sun KH, Chang KH, Clawson S, Ghosh, S, Mirzaei H, Regnier, F, Shah K. (2011) Glutathione S-transferase P1 is a Critical Regulator of Cdk5 Kinase Activity. J Neurochem 118(5), 902-14. Chang KH, Multani PS, Sun KH, Vincent F, de Pablo Y, Ghosh S, Gupta R, Lee HP, Lee HG, Smith MA, Shah K. (2011) Nuclear Envelope Dispersion Triggered by Deregulated Cdk5 Precedes Neuronal Death. Mol Biol Cell 22(9), 1452-62. Kumar D, Patel G, Chavers A, Chang KH, Shah K. (2011) Synthesis of novel 1,2,4-oxadiazoles and analogues as potential anticancer agents. European Journal of Medicinal Chemistry 46(7), 3085-92. Kumar D, Vadulla BR, Chang KH, Shah K. (2011) One-pot synthesis and anticancer studies of 2-arylamino-5-aryl-1,3,4-thiadiazoles. Bioorg Med Chem Lett 21(8), 2320-3. Kumar D, Kumar NM, Chang KH, Shah K. (2011) Synthesis of Novel Indolyl-1,2,4-triazoles as Potent and Selective Anticancer Agents. Chem Biol Drug Design 77, 182-8. Kumar D, Maruthi Kumar N, Chang KH, Shah K. (2010) Synthesis and anticancer activity of 5-(3-indolyl)-1,3,4-thiadiazoles. Eur J Med Chem. 45(10):4664-8. Chang KH, Pablo Y, Lee H, Lee H, Smith M, Shah K. (2010) Cdk5 is a Major Regulator of p38 Cascade: Relevance to Neurotoxicity in Alzheimer’s Disease. J Neurochem 113(5):1221-9. Kumar D, Kumar M, Sundaree S, Johnson E, Shah K. (2010) An expeditious synthesis and anticancer activity of novel 4-(3'-indolyl)oxazoles. Eur J Med Chem 45(3):1244-9. Sun KH, Lee HG, Smith MA, Shah, K. (2009) Direct and Indirect Roles of Cdk5 as an Upstream Regulator in the JNK Cascade: Relevance to Neurotoxic Insults in Alzheimer’s Disease. Mol Biol Cell 20(21):4611-9. Das M, Wiley DJ, Chen X, Shah K, Verde F. (2009) The conserved NDR kinase Orb6 controls polarized cell growth by spatial regulation of the small GTPase Cdc42. Current Biology 19, 1314-9. Kumar D, Sundaree S, Johnson, E, Shah, K. (2009) An efficient synthesis and biological study of novel indolyl-1,3,4-oxadiazoles as potent anticancer agents. Bioorg Med Chem Lett. 19(15), 4492-4. Kumar D, Patel G, Johnson, E, Shah, K. (2009) Synthesis and anticancer activities of novel 3,5-disubstituted-1,2,4-oxadiazoles. Bioorg Med Chem Lett, 19(10), 2739-41. Sun KH, de Pablo Y, Vincent F, Shah K. (2008) Deregulated Cdk5 Promotes Oxidative Stress and Mitochondrial Dysfunction. J Neurochem. 107: 265-278. Sun KH, de Pablo Y, Vincent F, Johnson EO, Chavers AK, Shah K. (2008) Novel Genetic Tools Reveal Cdk5's Major Role in Golgi Fragmentation in Alzheimer's Disease. Mol Biol Cell. 19(7):3052-69. Vincent F, Cook S, Johnson EO, Emmert D, Shah K. (2007) Engineering Unnatural Nucleotide Specificity to Probe G protein Signaling. Chem Biol. 14(9), 1007-18. (Research Highlights: Stevens K. (2007) “Designer Modulators” Nature Methods 4(12): 988; Review: Erickson JW, Cerione RA.(2008) “A new tool for G protein analysis” ACS Chem Biol. 3(1):24-6.)