Ajay Rana, Ph.D.
Ajay Rana, Ph.D.
Associate Professor
Office: Bldg 101, Room 2700 Phone: 708-216-5761 Fax: 708-216-6596
Education: Indian Institute of Chemical Biology, Jadavpur University, Calcutta, India
Primary Research: Role of MAP kinases and phosphatases in cell growth, migration, metastasis, and cell death and survival pathways.
Research Abstract: The fine balance between cell survival and cell death pathways determines whether a cell will die or survive. Any dysregulation in this fine balance can eventually lead to pathological disorders, related to uncontrolled cell growth (i.e. cancer) or excess cell death (i.e. neurodegeneration). It is well appreciated that members of protein kinase family and phosphatases play a central role in maintaining this fine balance between death and survival.
Our research is focused to define the physiological roles of a novel family of Kinases, called Mixed Lineage Kinases (MLKs). We have previously demonstrated that MLK3, a member of MLK family activates Jun-N-terminal Kinases (JNKs). We also identified TNFα and Ceramide as specific agonists of MLK3. These findings collectively suggested us that probably MLK3 or other members of this family might be involved in regulating cell death pathway. Subsequently, our group and others have demonstrated that indeed activation of MLK3 leads to cell death, primarily in neuronal cells. Interestingly, TNFα and Ceramide both have been directly implicated in cell death pathways. Furthermore, it was shown that MLK group of Kinases mediate the dopaminergic neuronal cell death in a mouse model of Parkinson’s disease. These results suggested that MLK group of Kinases can be targeted for controlling dopaminergic neuronal loss during Parkinson’s disease. Infact the small molecule inhibitor of MLK group of Kinases, CEP-1347 and CEP-11004 prevented dopaminergic neuronal cell death in MPTP-mouse model of Parkinson’s disease. Our laboratory is focused to further dissect the detailed pathways by which MLKs mediate the dopaminergic cell death via recently identified ligands of MLK3, TNFα and Ceramide.
The second area that our laboratory is focused on is to define the role of MLK3 and other MLK members in oncogenesis. We use breast cancer as a model to delineate the role of MLKs in uncontrolled cell growth. We have observed that MLK3 is over expressed in primary breast tumors. We have also identified the downstream targets of MLK3 in breast cancer cell lines and tumors. Our future plan is to define how MLK3 and other MLKs in general play a paradoxical role in breast cancer tumors. We also plan to examine the role of estrogen receptor in MLKs-induced signaling.
Selected Publications:
Rana A, Gallo K, Godowski P, Hirai S, Ohno S, Zon L, Kyriakis J and Avruch J. The mixed lineage kinase SPRK phosphorylates and activates the stress-activated protein kinase activator, SEK-1. J Biol Chem. 1996; 271(32):19025-8.
Sathyanarayana P, Barthwal MK, Kundu CN, Lane ME, Bergmann A, Tzivion G and Rana A. Activation of the Drosophila MLK by ceramide reveals TNF-α and ceramide as agonists of mammalian MLK3. Mol. Cell. 2002; 10(6):1527-33.
Barthwal MK, Sathyanarayana P, Kundu CN, Rana B, Pradeep A, Sharma C, Woodgett JR and Rana A. Negative regulation of Mixed Lineage Kinase 3 (MLK3) by Protein Kinase B (AKT) leads to cell survival. J Biol Chem. 2003; 278 (6):3897-902.
Sathyanarayana P, Barthwal MK, Lane ME, Acevedo SF, Skoulakis EMC, Bergmann A and Rana A. Drosophila mixed lineage kinase, a missing biochemical link in Drosophila JNK signaling. Biochim Biophys Acta. 2003; 1640 (1): 77-84.
Mishra R, Barthwal MK, Sondarva G, Rana B, Wong L, Chatterjee M, Woodgett JR and Rana A. Glycogen synthase kinase-3beta induces neuronal cell death via direct phosphorylation of Mixed Lineage Kinase 3. J Biol Chem. 2007; 282(42): 30393-405.