Ajay Rana
  • Professor
  • Molecular Pharmacology and Therapeutics
Research Summary

Role of MAP kinases in cell death and survival pathways

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 TNFa 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, TNFa 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, TNFa 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.


AKT and 14-3-3 Regulate Notch4 Nuclear LocalizationRamakrishnan,G.; Davaakhuu,G.; Chung,W. C.; Zhu,H.; Rana,A.; Filipovic,A.; Green,A. R.; Atfi,A.; Pannuti,A.; Miele,L.; Tzivion,G.Scientific reports 2015 ;5( ):8782

Histone Hyperacetylation Upregulates PKCdelta in Dopaminergic Neurons to Induce Cell Death: Relevance to Epigenetic Mechanisms of Neurodegeneration in Parkinson's DiseaseJin,H.; Kanthasamy,A.; Harischandra,D. S.; Kondru,N.; Ghosh,A.; Panicker,N.; Anantharam,V.; Rana,A.; Kanthasamy,A. G.The Journal of biological chemistry 2014 ; ( ):

Alpha-synuclein induces lysosomal rupture and cathepsin dependent reactive oxygen species following endocytosisFreeman,D.; Cedillos,R.; Choyke,S.; Lukic,Z.; McGuire,K.; Marvin,S.; Burrage,A. M.; Sudholt,S.; Rana,A.; O'Connor,C.; Wiethoff,C. M.; Campbell,E. M.PLoS ONE 2013 ;8(4):e62143

Mixed-lineage kinase 3 phosphorylates prolyl-isomerase Pin1 to regulate its nuclear translocation and cellular function.Rangasamy,V.; Mishra,R.; Sondarva,G.; Das,S.; Lee,T. H.; Bakowska,J. C.; Tzivion,G.; Malter,J. S.; Rana,B.; Lu,K. P.; Kanthasamy,A.; Rana,A.Proceedings of the National Academy of Sciences of the United States of America 2012 ;109(21):8149-8154

Mixed lineage kinase 3 modulates beta-catenin signaling in cancer cellsThylur,R. P.; Senthivinayagam,S.; Campbell,E. M.; Rangasamy,V.; Thorenoor,N.; Sondarva,G.; Mehrotra,S.; Mishra,P.; Zook,E.; Le,P. T.; Rana,A.; Rana,B.The Journal of biological chemistry 2011 ;286(43):37470-37482

TRAF2-MLK3 interaction is essential for TNF-alpha-induced MLK3 activation.Sondarva,G.; Kundu,C. N.; Mehrotra,S.; Mishra,R.; Rangasamy,V.; Sathyanarayana,P.; Ray,R. S.; Rana,B.; Rana,A.Cell research 2010 ;20(1):89-98

How estrogen fuels breast cancerRana,A.; Rangasamy,V.; Mishra,R.Future Oncology 2010 ;6(9):1369-1371

Estrogen suppresses MLK3-mediated apoptosis sensitivity in ER+ breast cancer cells.Rangasamy,V.; Mishra,R.; Mehrotra,S.; Sondarva,G.; Ray,R. S.; Rao,A.; Chatterjee,M.; Rana,B.; Rana,A.Cancer research 2010 ;70(4):1731-1740

Caspase-mediated cleavage of beta-catenin precedes drug-induced apoptosis in resistant cancer cells.Senthivinayagam,S.; Mishra,P.; Paramasivam,S. K.; Yallapragada,S.; Chatterjee,M.; Wong,L.; Rana,A.; Rana,B.Journal of Biological Chemistry 2009 ;284(20):13577-13588

Carcinogen-induced early molecular events and its implication in the initiation of chemical hepatocarcinogenesis in rats: chemopreventive role of vanadium on this process.Chakraborty,T.; Chatterjee,A.; Rana,A.; Dhachinamoorthi,D.; Kumar,P. A.; Chatterjee,M.Biochimica et biophysica acta 2007 ;1772(1):48-59

Suppression of early stages of neoplastic transformation in a two-stage chemical hepatocarcinogenesis model: supplementation of vanadium, a dietary micronutrient, limits cell proliferation and inhibits the formations of 8-hydroxy-2'-deoxyguanosines and DNA strand-breaks in the liver of sprague-dawley rats.Chakraborty,T.; Chatterjee,A.; Rana,A.; Rana,B.; Palanisamy,A.; Madhappan,R.; Chatterjee,M.Nutrition & Cancer 2007 ;59(2):228-247

Suppression of cell proliferation, induction of apoptosis and cell cycle arrest: chemopreventive activity of vanadium in vivo and in vitro.Ray,R. S.; Ghosh,B.; Rana,A.; Chatterjee,M.International Journal of Cancer 2007 ;120(1):13-23

Glycogen synthase kinase-3beta induces neuronal cell death via direct phosphorylation of mixed lineage kinase 3.Mishra,R.; Barthwal,M. K.; Sondarva,G.; Rana,B.; Wong,L.; Chatterjee,M.; Woodgett,J. R.; Rana,A.Journal of Biological Chemistry 2007 ;282(42):30393-30405

Peroxisome proliferator-activated receptor gamma activation can regulate beta-catenin levels via a proteasome-mediated and adenomatous polyposis coli-independent pathway.Sharma,C.; Pradeep,A.; Wong,L.; Rana,A.; Rana,B.Journal of Biological Chemistry 2004 ;279(34):35583-35594

Negative regulation of mixed lineage kinase 3 by protein kinase B/AKT leads to cell survival.Barthwal,M. K.; Sathyanarayana,P.; Kundu,C. N.; Rana,B.; Pradeep,A.; Sharma,C.; Woodgett,J. R.; Rana,A.Journal of Biological Chemistry 2003 ;278(6):3897-3902