Nupam <span>P.</span> Mahajan, PhD
Researcher

Nupam P. Mahajan, PhD

Academic Rank: Associate Member

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Overview

A major interest in our lab is to determine the role of tyrosine kinases in modulating signaling pathways and as epigenetic modifiers in cancer and other diseases.

Discipline

    • Drug Discovery
    • Genitourinary Oncology
    • Cancer Chemoprevention Research Interest Group
    • Melanoma Research Center of Excellence
    • Lung Cancer Center of Excellence
    • Chemical Biology and Molecular Medicine Program

Education & Training

    • Indian Institute of Science, India, PhD - Molecular Biology
    • University of North Carolina, Chapel Hill, NC, Postdoctoral Fellow - Cell Biology
Research

We employ two tyrosine kinases, WEE1 and Ack1 (TNK2) to investigate signaling and epigenetic processes. Some of the major findings of our lab include: We demonstrated for the first time that WEE1 kinase is an epigenetic modifier; it phosphorylates histone H2B at Tyrosine 37 in a cell cycle dependent manner. H2B Ty37-phosphorylation suppressed transcription of all core and linker histones, maintaining equimolar ratio of DNA to histones at the end of S phase. WEE1 mediated H2B Tyr37-phosphorylation acts as a switch to initiate transcriptional shutdown by recruiting repressors like HIRA and excluding the coactivator NPAT and RNA Pol II. We demonstrated that Ack1 is activated in various tumors, including prostate, breast and pancreatic cancer.  We identified multiple effectors of Ack1 signaling; AR, AKT, ATM and Wwox. Addiction of cancerous cells to Ack1 signaling was validated by a small molecular inhibitor, AIM-100. We identified a novel phosphorylation site, Tyrosine 176, in AKT. AKT Tyr176-phosphyrlation correlates with breast, lung and pancreatic cancer progression to metastatic stages. the Tyr267-phosphorylated AR initiated a distinct transcriptional program, critical for androgen-independent growth of prostate cancer (also called CRPC) and promotes radioresistance.  

Publications

  • Mahajan K, Malla P, Lawrence HR, Chen Z, Kumar-Sinha C, Malik R, Shukla S, Kim J, Coppola D, Lawrence NJ, Mahajan NP. ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer. Cancer Cell. 2017 Jun;31(6):790-803.e8. Pubmedid: 28609657. Pmcid: PMC5512571.
  • Wu X, Zahari MS, Renuse S, Kelkar DS, Bharbuiya MA, Rojas PL, Stearns V, Gabrielson E, Malla P, Sukumar S, Mahajan NP, Pandey A. The non-receptor tyrosine kinase TNK2/ACK1 is a novel therapeutic target in triple negative breast cancer. Oncotarget. 2017 Jan;8(2):2971-2983. Pubmedid: 27902967. Pmcid: PMC5356856.
  • Paranjape AN, Soundararajan R, Werden SJ, Joseph R, Taube JH, Liu H, Rodriguez-Canales J, Sphyris N, Wistuba I, Miura N, Dhillon J, Mahajan N, Mahajan K, Chang JT, Ittmann M, Maity SN, Logothetis C, Tang DG, Mani SA. Inhibition of FOXC2 restores epithelial phenotype and drug sensitivity in prostate cancer cells with stem-cell properties. Oncogene. 2016 Nov;35(46):5963-5976. Pubmedid: 26804168. Pmcid: PMC5116559.
  • Lawrence HR, Mahajan K, Luo Y, Zhang D, Tindall N, Huseyin M, Gevariya H, Kazi S, Ozcan S, Mahajan N, Lawrence NJ. Development of novel ACK1/TNK2 inhibitors using a fragment-based approach. J Med Chem. 2015 Mar;58(6):2746-2763. Pubmedid: 25699576. Pmcid: PMC4605435.
  • Mahajan K, Mahajan NP. Cross talk of tyrosine kinases with the DNA damage signaling pathways. Nucleic Acids Res. 2015 Dec;43(22):10588-10601. Pubmedid: 26546517. Pmcid: PMC4678820.
  • Mahajan K, Mahajan NP. ACK1/TNK2 tyrosine kinase: molecular signaling and evolving role in cancers. Oncogene. 2015 Aug;34(32):4162-4167. Pubmedid: 25347744. Pmcid: PMC4411206.
  • Mahajan K, Lawrence HR, Lawrence NJ, Mahajan NP. ACK1 tyrosine kinase interacts with histone demethylase KDM3A to regulate the mammary tumor oncogene HOXA1. J Biol Chem. 2014 Oct;289(41):28179-28191. Pubmedid: 25148682. Pmcid: PMC4192474.
  • Mahajan KN, Mahajan NP. AKT goes cycling. Cancer Control. 2014 Jul;21(3):239-241. Pubmedid: 24955708. Pmcid: PMC4181845.
  • Mahajan K, Mahajan NP. ACK1 tyrosine kinase: targeted inhibition to block cancer cell proliferation. Cancer Lett. 2013 Sep;338(2):185-192. Pubmedid: 23597703. Pmcid: PMC3750075.
  • Buchwald M, Pietschmann K, Brand P, Günther A, Mahajan NP, Heinzel T, Krämer OH. SIAH ubiquitin ligases target the nonreceptor tyrosine kinase ACK1 for ubiquitinylation and proteasomal degradation. Oncogene. 2013 Oct;32(41):4913-4920. Pubmedid: 23208506. Pmcid: PMC3731393.
  • Linderoth E, Pilia G, Mahajan N, Ferby I. Activated Cdc42-associated kinase 1 (Ack1) is required for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor recruitment to lipid rafts and induction of cell death. J Biol Chem. 2013 Nov;288(46):32922-32931. Pubmedid: 24085293. Pmcid: PMC3829143.
  • Mahajan K, Mahajan NP. WEE1 tyrosine kinase, a novel epigenetic modifier. Trends Genet. 2013 Jul;29(7):394-402. Pubmedid: 23537585. Pmcid: PMC3700603.
  • Mahajan K, Mahajan NP. PI3K-independent AKT activation in cancers: a treasure trove for novel therapeutics. J Cell Physiol. 2012 Sep;227(9):3178-3184. Pubmedid: 22307544. Pmcid: PMC3358464.
  • Mahajan K, Fang B, Koomen JM, Mahajan NP. H2B Tyr37 phosphorylation suppresses expression of replication-dependent core histone genes. Nat Struct Mol Biol. 2012 Sep;19(9):930-937. Pubmedid: 22885324. Pmcid: PMC4533924.
  • Mahajan K, Coppola D, Rawal B, Chen YA, Lawrence HR, Engelman RW, Lawrence NJ, Mahajan NP. Ack1-mediated androgen receptor phosphorylation modulates radiation resistance in castration-resistant prostate cancer. J Biol Chem. 2012 Jun;287(26):22112-22122. Pubmedid: 22566699. Pmcid: PMC3381169.
  • Kumar NB, Vadaparampil ST, Mahajan N, Lilienfeld HS, Lee JH, Laronga C, Hakam A, Hein JJ, Egan KM, Arun B, Pal T. Metformin- A Promising Agent for Chemoprevention in BRCA1 Carriers. Hereditary Genet. 2012 Jun;1(2). Pubmedid: 26097796. Pmcid: PMC4474476.
  • Mahajan K, Coppola D, Chen YA, Zhu W, Lawrence HR, Lawrence NJ, Mahajan NP. Ack1 tyrosine kinase activation correlates with pancreatic cancer progression. Am J Pathol. 2012 Apr;180(4):1386-1393. Pubmedid: 22322295. Pmcid: PMC3349895.
  • Lin HY, Park HY, Radlein S, Mahajan NP, Sellers TA, Zachariah B, Pow-Sang J, Coppola D, Ganapathy V, Park JY. Protein expressions and genetic variations of SLC5A8 in prostate cancer risk and aggressiveness. Urology. 2011 Oct;78(4):971.e1-971.e9. Pubmedid: 21802122. Pmcid: PMC3190039.
  • Mahajan K, Challa S, Coppola D, Lawrence H, Luo Y, Gevariya H, Zhu W, Chen YA, Lawrence NJ, Mahajan NP. Effect of Ack1 tyrosine kinase inhibitor on ligand-independent androgen receptor activity. Prostate. 2010 Sep;70(12):1274-1285. Pubmedid: 20623637. Pmcid: PMC3953126.
  • Mahajan K, Coppola D, Challa S, Fang B, Chen YA, Zhu W, Lopez AS, Koomen J, Engelman RW, Rivera C, Muraoka-Cook RS, Cheng JQ, Schönbrunn E, Sebti SM, Earp HS, Mahajan NP. Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation. PLoS One. 2010 Mar;5(3):e9646. Pubmedid: 20333297. Pmcid: PMC2841635.
  • Mahajan K, Mahajan NP. Shepherding AKT and androgen receptor by Ack1 tyrosine kinase. J Cell Physiol. 2010 Aug;224(2):327-333. Pubmedid: 20432460. Pmcid: PMC3953130.
  • Mahajan NP, Liu Y, Majumder S, Warren MR, Parker CE, Mohler JL, Earp HS, Whang YE. Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation. Proc Natl Acad Sci U S A. 2007 May;104(20):8438-8443. Pubmedid: 17494760. Pmcid: PMC1895968.
  • Mahajan NP, Whang YE, Mohler JL, Earp HS. Activated tyrosine kinase Ack1 promotes prostate tumorigenesis: role of Ack1 in polyubiquitination of tumor suppressor Wwox. Cancer Res. 2005 Nov;65(22):10514-10523. Pubmedid: 16288044.
  • Li Y, Mahajan NP, Webster-Cyriaque J, Bhende P, Hong GK, Earp HS, Kenney S. The C-mer gene is induced by Epstein-Barr virus immediate-early protein BRLF1. J Virol. 2004 Nov;78(21):11778-11785. Pubmedid: 15479819. Pmcid: PMC523243.
  • Mahajan NP, Earp HS. An SH2 domain-dependent, phosphotyrosine-independent interaction between Vav1 and the Mer receptor tyrosine kinase: a mechanism for localizing guanine nucleotide-exchange factor action. J Biol Chem. 2003 Oct;278(43):42596-42603. Pubmedid: 12920122.
  • Guttridge KL, Luft JC, Dawson TL, Kozlowska E, Mahajan NP, Varnum B, Earp HS. Mer receptor tyrosine kinase signaling: prevention of apoptosis and alteration of cytoskeletal architecture without stimulation or proliferation. J Biol Chem. 2002 Jul;277(27):24057-24066. Pubmedid: 11929866.
  • Mahajan K, Gangi-Peterson L, Sorscher D, Wang J, Gathy K, Mahajan N, Reeves W, Mitchell B. Association of terminal deoxynucleotidyl transferase with Ku. Proc Natl Acad Sci U S A. 1999 Nov;96(24):13926-13931. Pubmedid: 10570175. Pmcid: PMC24167.
  • Mahajan N, Harrison-Shostak D, Michaux J, Herman B. Novel mutant green fluorescent protein protease substrates reveal the activation of specific caspases during apoptosis. Chem Biol. 1999 Jun;6(6):401-409. Pubmedid: 10375546.
  • Mahajan N, Linder K, Berry G, Gordon G, Heim R, Herman B. Bcl-2 and Bax interactions in mitochondria probed with green fluorescent protein and fluorescence resonance energy transfer. Nat Biotechnol. 1998 Jun;16(6):547-552. Pubmedid: 9624685 .
  • Zha H, Fisk H, Yaffe M, Mahajan N, Herman B, Reed J. Structure-function comparisons of the proapoptotic protein Bax in yeast and mammalian cells. Mol Cell Biol. 1996 Nov;16(11):6494-6508. Pubmedid: 8887678 .
  • Mahajan N, Rao C. Nucleotide sequence and expression in E. coli of the complete P4 type VP4 from a G2 serotype human rotavirus. Arch Virol. 1996;141(2):315-329. Pubmedid: 8634023 .
  • Rajani A, Dash KK, Mahajan NP, Kumar R. Bilateral Spontaneous Midsubstance Patellar Tendon Rupture after Bilateral Total Knee Arthroplasty. J Orthop Case Rep. 6(2):75-77. Pubmedid: 27703942. Pmcid: PMC5040580.