Neuronal Cytoskeletal Protein Regulation Section - Division of Intramural Research
Harish C. Pant, Ph.D., Senior Investigator
Dr. Pant received his M.A. and Ph.D. degrees in Physics from Agra University, Agra, India. His postdoctoral studies were conducted on the mechanisms of electron and ion transport in model membrane systems at the Department of Biophysics at Michigan State University. He joined the Laboratory of Neurobiology in the NIMH as a senior staff fellow in 1974 with Dr. Ichiji Tasaki where he studied the function of the axonal cytoskeleton in the squid giant axon. In 1979 he moved to the NIAAA extending his studies on the neuronal cytoskeleton and the effects of alcohol on its regulation. Dr. Pant moved to the NINDS, Laboratory of Neurochemistry in 1987 where he is presently chief of the section on Cytoskeleton Regulation. His laboratory is studying the mechanisms of topographic regulation of neuronal cytoskeleton proteins by post-translational modification, including the role of kinase cascades in normal brain and during neurodegeneration.
, Ph.D., Research Fellow
The major focus of this laboratory has been to study the mechanisms of topographic regulation of neuronal cytoskeletal proteins regulation by phosphorylation and neurodegeneration.
In a normal physiological state, cytoskeletal proteins are phosphorylated extensively in the axonal compartment of a mature neuron. Although all the substrates, kinases, phosphatases and their regulators are synthesized in neuronal cell bodies, little or no cytoskeletal protein phosphorylation has been detected in the cell body compartment. Under a variety of neuropathological conditions, however, such as ALS, Alzheimers Disease, or Picks disease, hyperphosphorylation of these molecules has been found in abnormal aggregates within cell bodies, usually correlated with massive neuronal cell death. The mechanisms underlying these profound compartmental shifts in neuronal phosphorylation are not well understood.The normal physiological processes within neurons are controlled by signal transduction mechanisms that regulate the balance between protein kinase and protein phosphatase activities. We have shown that the most abundant and extensively phosphorylated motifs in the c-terminal domains (lys-ser-pro-, or KSP) are primarily phosphorylated by proline directed kinases, cdk5 and MAP kinases. Moreover, we have demonstrated that this phosphorylation is due to activation of the signal transduction cascade. Recently, we have focussed on the other part of this regulation, the protein phosphatases. The other project is to study the expression, regulation and role of neuronal Cdk5 in nerve cell function.Cdk5 is a unique multifunctional kinase. Unlike other cyclin-dependent kinases, it is expressed predominantly in post-mitotic neurons, its activity modulated by association with nervous system-specific propeins. Since its identification and characterization in our laboratory, we have been intensively studying its mechanisms of regulation and its role in nerve cell function.
Selected Recent Publications
Amin ND, Zheng YL, Kesavapany S, Kanungo J, Guszczynski T, Sihag RK, Rudrabhatla P, Albers W, Grant P, Pant HC.
Cyclin-dependent kinase 5 phosphorylation of human septin SEPT5 (hCDCrel-1) modulates exocytosis., J Neurosci., 2008, vol. 28(14), pp. 3631-43.
Kesavapany S, Patel V, Zheng YL, Pareek TK, Bjelogrlic M, Albers W, Amin N, Jaffe H, Gutkind JS, Strong MJ, Grant P, Pant HC.
Inhibition of Pin1 reduces glutamate-induced perikaryal accumulation of phosphorylated neurofilament-H in neurons., Mol Biol Cell, 2007, vol. 18(9), pp. 3645-55.
Kino T, Ichijo T, Amin ND, Kesavapany S, Wang Y, Kim N, Rao S, Player A, Zheng YL, Garabedian MJ, Kawasaki E, Pant HC, Chrousos
Cyclin-dependent kinase 5 differentially regulates the transcriptional activity of the glucocorticoid receptor through phosphorylation: clinical implications for the nervous system response to glucocorticoids and stress., Mol Endocrinol., 2007, vol. 21(7), pp. 1552-68.
Pareek TK, Keller J, Kesavapany S, Agarwal N, Kuner R, Pant HC, Iadarola MJ, Brady RO, Kulkarni AB.
Cyclin-dependent kinase 5 modulates nociceptive signaling through direct phosphorylation of transient receptor potential vanilloid 1., Proc Natl Acad Sci U S A, 2007, vol. 104(2), pp. 660-5.
Kesavapany S, Pareek TK, Zheng YL, Amin N, Gutkind JS, Ma W, Kulkarni AB, Grant P, Pant HC.
Neuronal nuclear organization is controlled by cyclin-dependent kinase 5 phosphorylation of Ras Guanine nucleotide releasing factor-1., Neurosignals, 2007, vol. 15(4), pp. 157-73.
Sihag RK, Inagaki M, Yamaguchi T, Shea TB, Pant HC.
Role of phosphorylation on the structural dynamics and function of types III and IV intermediate filaments., Exp Cell Res., 2007, vol. 313(10), pp. 2098-109.
Zheng YL, Li BS, Kanungo J, Kesavapany S, Amin N, Grant P, Pant HC.
Cdk5 Modulation of mitogen-activated protein kinase signaling regulates neuronal survival., Mol Biol Cell., 2007, vol. 18(2), pp. 404-13.
Kesavapany S, Zheng YL, Amin N, Pant HC.
Peptides derived from Cdk5 activator p35, specifically inhibit deregulated activity of Cdk5., Biotechnol J., 2007, vol. 2(8), pp. 978-87.
Selected Earlier Publications