Shenolikar, Shirish

Research Interests:

Our primary research is directed at understanding protein phosphatases : how these signaling enzymes are controlled by physiological stimuli and how they specify the changes in protein phosphorylation that dictate the cell’s response to hormones, neurotransmitters and growth factors. A key driver for this research is the observation that phosphatases are often deregulated in human cancers, diabetes, reproductive disorders and neurological disease. Our current studies are focused on a cell signaling pathway controlled by the stress-response gene, GADD34 (Growth Arrest and DNA-Damage-inducible gene). Our work attempts to decipher how cells detect and respond to transient or acute stress, caused by nutrient deprivation, ischemia, heat shock and UV irradiation, to control protein synthesis in mammalian cells. The specific goal of the ongoing work is to elucidate the cellular mechanisms that control the transcription, translation and covalent modification of GADD34 and establish how this directs the cell’s decision to survive or die. Emerging evidence indicate that pharmacological inhibition of GADD34 function ameliorates disease manifestations associated with epilepsy, muscular dystrophy, motoneruon disease and neurodegeneration. As stress response pathways activated in many human diseases, our research hopes to provide vital information on the genesis of cancer, diabetes, cardiovascular and neurological diseases.

A second project is focused on the use of genetically modified mice to understand the physiological role of the adapter or scaffolding proteins, NHERF-1 and NHERF-2, in membrane protein trafficking and signaling by G-protein-coupled receptors in the mammalian kidney.

Students and fellows in this lab are encouraged to utilize a multidisciplinary approach, employing techniques of molecular and structural biology, protein biochemistry and biophysics, cell biology and genetics, to elucidate cell signaling mechanisms and understand the detrimental effects of altered signal transduction in cellular and animal models of human disease.

Selected Publications:

Zhou, W*., Brush, M.H*., Choy, M.S. and Shenolikar, S. (2011) Association with Endoplasmic Reticulum Enhances GADD34 Turnover. J. Biol. Chem. In press. (*Equal contributions).

Weinman, E.J., Biswas, R., Steplock, D., Wang P., Lau, Y.S., Desir, G.V. and Shenolikar S. (2011) Increased renal dopamine and acute renal adaptation to a high-phosphate diet. Am J Physiol Renal Physiol. 300:F1123-9.

Weinman, E.J, Steplock, D., Shenolikar, S. and Blanpied T.A. (2011) Dynamics of PTH-induced disassembly of Npt2a/NHERF-1 complexes in living OK cells. Am. J. Physiol. Cell Physiol. 300:F231-235.

Cunningham R, Biswas R, Steplock D, Shenolikar S., Weinman E. (2010) Role of NHERF and scaffolding proteins in proximal tubule transport. Urol. Res. 38:257-262

Weinman, E.J., Steplock, D., Zhang, Y., Biswas, R., Bloch, RJ and Shenolikar, S. (2010) Cooperativity between the phosphorylation of Thr95 and Ser77 of NHERF-1 in the hormonal regulation of renal phosphate transport. J. Biol. Chem 285:25134-25138.

Weinman, E.J., Biswas, R., Steplock, D., Douglas, T., Cunningham, C. and Shenolikar, S. (2010) NHERF-1 is required for dopamine-mediated inhibition of renal phosphate transport. J. Biol. Chem. 285:13454-13460.

Weinman, E.J., Steplock, D., Cha, B., Frost, N.A., Cunningham, R., Shenolikar, S., Blanpied, T.A. and Donowitz, M. (2009) PTH transiently increases the percent mobile fraction of Npt2a in OK Cells as determined by FRAP. Am J Physiol. Renal Physiol. 297:F1560-1565.

Virshup, D.M. and Shenolikar, S. (2009) From Promiscuity to Precision : Protein Phosphatases Get a Makeover. Mol. Cell. 33: 537-545.

Cunningham, R., Biswas, R., Brazie, M., Steplock, D., Shenolikar, S., and Weinman, E.J. (2009) Signaling pathways utilized by PTH and dopamine to inhibit phosphate transport in mouse renal proximal tubule cells. Am J Physiol Renal Physiol, 296: F355 - F361.

Brush, M.H. and Shenolikar, S. (2008) Control of cellular GADD34 Levels by the 26S Proteasome. Mol. Cell. Biol. 28:6989-7000.

Esmail, A., Brown, E., Wang, F., Steplock, D., Cunningham, R., Murtaina, R., Donowitz, M., Hogema, B., De Jonge, H., Shenolikar, S., Wade, J.B., and Weinman, E.J. (2008) Urine electrolyte, mineral and protein excretion in NHERF-1 and NHERF-2 null mice. Am. J. Physiol. Cell Physiol 294: F1001 - F1007.