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Medicine

Pathology

Faculty

Faculty

Parameswaran Ramakrishnan, M.S., Ph.D.

Parameswaran Ramakrishnan, M.S., Ph.D.

Assistant Professor

pxr150@case.edu (216) 368-2387 (o) (216) 368-0494 (f)

Parameswaran Ramakrishnan obtained his B.Sc and M.Sc in Biotechnology degrees from Mahatma Gandhi University, India in 1993 and 1996 respectively. Later he worked in an Indo-Swiss collaborative project studying the genome diversity in Mycobacterium leprae in the Department of Biotechnology, Madurai Kamaraj University, India, until the end of 1999. He joined Weizmann Institute of Science, Israel, for his research toward Ph.D. under the guidance of Prof. David Wallach and studied signal transduction in the immune system with a focus on mechanisms involved in the regulation and function of the protein, NF-κB inducing kinase. After attaining a Ph.D. in 2005, he continued as a postdoctoral fellow and studied ubiquitination and proteasomal degradation of molecules in the NF-κB signaling pathway till the end of 2007. Dr. Ramakrishnan joined the lab of Prof. David Baltimore in the Department of Biology at California Institute of Technology in 2008. While in Baltimore lab, Dr. Ramakrishnan studied regulation of NF-κB activation by posttranslational modifications and the RNA-binding adaptor protein, Sam68. He studied the unique intracellular glycosylation called O-GlcNAc glycosylation, which is induced under hyperglycemic conditions, such as diabetes. This study was supported by a grant from Mizutani Foundation for Glycosciences, Japan. Dr. Ramakrishnan joined Case Western Reserve University's Department of Pathology in the summer of 2013.

Research summary

Dr. Ramakrishnan's lab focuses on signal transduction in immunity, metabolism and cancer using cellular and molecular approaches and animal models with the aim of identifying fundamental mechanisms leading to development and evaluation of therapeutic targets.

Research projects
NF-κB is known to be a family of dimeric transcription factor that act as a key regulator of the immune and inflammatory responses. Because inflammation has been linked to so many diseases in recent times, there is much interest in the role of NF-κB in autoimmune conditions like diabetes and cancer.

Regulation of NF-κB activity by O-GlcNAc glycosylation and its role in diabetes
Significance: NF-κB is a preformed protein and its activation is dependent on posttranslational regulations. O-GlcNAcylation is a reversible intracellular protein modification whose levels are affected by glucose and other signals. Both O-GlcNAcylation and NF-κB activation has been associated in several physiological and pathological conditions including experimental and clinical diabetes, yet a direct link between them is missing and glycosylation of NF-κB by O-GlcNAc remains poorly defined.

Aims
To identify O-GlcNAcylated NF-κB proteins, the site(s) of modification and study this process both structurally and functionally, under physiological and pathological conditions.
To determine the role of O-GlcNAcylation of NF-κB in vivo using transgenic and knockout mouse models.

Role of Sam68 in inflammatory signaling, diabetes and associated cancer
Significance: Sam68 plays crucial role in innate immune and apoptotic signaling by tumor necrosis factor, TNF. This novel finding links Sam68 function in inflammatory and autoimmune diseases as well as inflammation induced cancer where deregulated TNF signaling is implicated.

Aims
To understand the molecular determinants of Sam68 function and its role in inflammatory signaling.
To study the physiological role of Sam68 in vivo in the immune system and delineate the RNA binding independent functions of Sam68.

Dynamic regulation of signaling in the immune system by protein modifications

Farabaugh, K, Majumder, M, Bo-Jhih Guan, Wu, J, Krokowski, D, Xing-Huang Gao, Schuster, A, Longworth, M, Josephine Kam Tai Dermawan, Chan, E, Bussolati, O, Ramakrishnan, P*, Hatzoglou, M (2017). PKR exacerbates proinflammatory gene expression and promotes experimental colitis. Feb 1;37(4). pii: e00521-16. doi: 10.1128/MCB.00521-16. Print 2017 Feb 15. PMID: 27920257. Co-corresponding Author.

Tomalka, J, de Jesus, TJ, Ramakrishnan, P*. (2016). Sam68 is a Regulator of Toll Like Receptor Signaling, Cell Mol Immunol. Cell Mol Immunol. 2017 Jan;14(1):107-117. doi: 10.1038/cmi.2016.32. Epub 2016 Jul 4. PMID: 27374795.

Ramakrishnan, P*, Yui, M, Tomalka, J, Majumdar, D, Parameswaran R, Baltimore, D. (2016). Deficiency of NF-kappaB c-Rel accelerates the development of autoimmune diabetes in non obese diabetic mice. Diabetes. 2016 Aug;65(8):2367-79. doi: 10.2337/db15-1607. Epub 2016 May 23. PMID: 27217485, Co-corresponding Author.

Parameswaran R, Ramakrishnan P, De Lima M, Lee DA, Moreton S and Wald DN. Repression of GSK3 restores NK cell cytotoxicity in AML patients. Nature Communications, Nat Commun. 2016 Apr 4;7:11154. doi: 10.1038/ncomms11154, PMID: 27040177 PMCID: PMC4822012.

de Jesus TJ and Ramakrishnan P*. Sugar-Coating the Skin. Austin Journal of Clinical Pathology. 2015 Nov; 2(3): 1035.

So, A.Y., Chaudhuri, A., Sookram, R., Minisandram, A., Cheng, D., Xie, C., Lim, L., Garcia Flores, Y., Jiang, S., Keown, C., Ramakrishnan, P., Baltimore, D. (2014), Dual mechanisms by which mir-125b represses IRF4 to cause myeloid and B-cell Leukemia. Blood. Jul 8. pii: blood-2014-02-553842. PMID: 25006123.

Ramakrishnan, P., Clark, PM., Mason, DE., Peters, ED., Hsieh-Wilson, LC and Baltimore, D. (2013). Activation of the Transcriptional Function of the NF-κB Protein c-Rel by O-GlcNAc Glycosylation. Science Signaling, August 27. Vol 6 Issue 290 ra75.

Yang, L., Boldin,M.P., Yu, Y., Liu,C.S., Ea.C.K., Ramakrishnan, P., Taganov,K.D., Zhao.J.L, and Baltimore.D (2012) miR-146a control of the resolution of T cell responses in mice. J Exp Med. Aug 27;209(9):1655-70.

Jevgenij A. Raskatov, Jordan L. Meier, James W. Puckett, Fei Yang, Ramakrishnan, P, and Peter B. Dervan. (2012) Modulation of NF-κB Dependent Gene Transcription Using Programmable DNA Minor Groove Binders. Proc Natl Acad Sci U S A. Jan 24;109(4):1023-8.

Ramakrishnan, P., Baltimore, D. (2011). Sam68 is Required for both NF-κB Activation and Apoptosis Signaling by the TNF receptor. Molecular Cell, Jul 22;43(2):167-79.

Ramakrishnan, P., Kahn, D., Baltimore, D. (2011) Anti-apoptotic effect of hyperglycemia can allow survival of potentially autoreactive T cells. Cell Death and Differentiation, April;18(4):690-9.

Citri A, Harari D, Shohat G, Ramakrishnan P, Gan J, Lavi S, Eisenstein M, Kimchi A, Wallach D, Pietrokovski S, Yarden Y. (2006) Hsp90 recognizes a common surface on client kinases. J Biol Chem. May 19;281(20):14361-9.

Sanchez-Valdepenas C, Martin AG, Ramakrishnan P, Wallach D, Fresno M. (2006). NF-κB-inducing kinase is involved in the activation of the CD28 responsive element through phosphorylation of c-Rel and regulation of its transactivating activity. J Immunol. Apr 15;176(8):4666-74.

Hauer, J., Puschner, S., Ramakrishnan, P., Simon, U., Bongers,M., Federle, C., and Engelmann, H. (2005). TNF receptor (TNFR)-associated factor (TRAF) 3 serves as an inhibitor of TRAF2/5-mediated activation of the noncanonical NF-κB pathway by TRAF-binding TNFRs. Proc Natl Acad Sci U S A 102, 2874-2879.

Ramakrishnan, P., Wang, W., and Wallach, D. (2004). Receptor-specific signaling for both the alternative and the canonical NF-κB activation pathways by NF-κB-inducing kinase. Immunity 21, 477-489.

Kang, T. B., Ben-Moshe, T., Varfolomeev, E. E., Pewzner-Jung, Y., Yogev, N., Jurewicz, A., Waisman, A., Brenner, O., Haffner, R., Gustafsson, E., Ramakrishnan, P., Lapidot, T., and Wallach, D. (2004). Caspase-8 serves both apoptotic and nonapoptotic roles. J Immunol 173, 2976-2984.