Browsing by Author "Nikiforov, Mikhail A"

Now showing 1 - 8 of 8
  • Thumbnail Image
    ItemOpen Access
    Compartmentalization and regulation of GTP in control of cellular phenotypes.
    (Trends in molecular medicine, 2022-09) Wolff, David W; Bianchi-Smiraglia, Anna; Nikiforov, Mikhail A
    Genetic or pharmacological inhibition of enzymes involved in GTP biosynthesis has substantial biological effects, underlining the need to better understand the function of GTP levels in regulation of cellular processes and the significance of targeting GTP biosynthesis enzymes for therapeutic intervention. Our current understanding of spatiotemporal regulation of GTP metabolism and its role in physiological and pathological cellular processes is far from complete. Novel methodologies such as genetically encoded sensors of free GTP offered insights into intracellular distribution and function of GTP molecules. In the current Review, we provide analysis of recent discoveries in the field of GTP metabolism and evaluate the key enzymes as molecular targets.
  • Thumbnail Image
    ItemOpen Access
    Inhibition of the aryl hydrocarbon receptor/polyamine biosynthesis axis suppresses multiple myeloma
    (Journal of Clinical Investigation, 2018-09-10) Bianchi-Smiraglia, Anna; Bagati, Archis; Fink, Emily E; Affronti, Hayley C; Lipchick, Brittany C; Moparthy, Sudha; Long, Mark D; Rosario, Spencer R; Lightman, Shivana M; Moparthy, Kalyana; Wolff, David W; Yun, Dong Hyun; Han, Zhannan; Polechetti, Anthony; Roll, Matthew V; Gitlin, Ilya I; Leonova, Katerina I; Rowsam, Aryn M; Kandel, Eugene S; Gudkov, Andrei V; Bergsagel, P Leif; Lee, Kelvin P; Smiraglia, Dominic J; Nikiforov, Mikhail A
  • Thumbnail Image
    ItemOpen Access
    Internally ratiometric fluorescent sensors for evaluation of intracellular GTP levels and distribution
    (Nature Methods, 2017-10) Bianchi-Smiraglia, Anna; Rana, Mitra S; Foley, Colleen E; Paul, Leslie M; Lipchick, Brittany C; Moparthy, Sudha; Moparthy, Kalyana; Fink, Emily E; Bagati, Archis; Hurley, Edward; Affronti, Hayley C; Bakin, Andrei V; Kandel, Eugene S; Smiraglia, Dominic J; Feltri, Maria Laura; Sousa, Rui; Nikiforov, Mikhail A
  • Thumbnail Image
    ItemOpen Access
    Melanoma Suppressor Functions of the Carcinoma Oncogene FOXQ1
    (Cell Reports, 2017-09) Bagati, Archis; Bianchi-Smiraglia, Anna; Moparthy, Sudha; Kolesnikova, Kateryna; Fink, Emily E; Lipchick, Brittany C; Kolesnikova, Masha; Jowdy, Peter; Polechetti, Anthony; Mahpour, Amin; Ross, Jason; Wawrzyniak, Joseph A; Yun, Dong Hyun; Paragh, Gyorgy; Kozlova, Nadezhda I; Berman, Albert E; Wang, Jianmin; Liu, Song; Nemeth, Michael J; Nikiforov, Mikhail A
  • Thumbnail Image
    ItemOpen Access
    Phosphorylation of guanosine monophosphate reductase triggers a GTP-dependent switch from pro- to anti-oncogenic function of EPHA4.
    (Cell chemical biology, 2022-06) Wolff, David W; Deng, Zhiyong; Bianchi-Smiraglia, Anna; Foley, Colleen E; Han, Zhannan; Wang, Xingyou; Shen, Shichen; Rosenberg, Masha M; Moparthy, Sudha; Yun, Dong Hyun; Chen, Jialin; Baker, Brian K; Roll, Matthew V; Magiera, Andrew J; Li, Jun; Hurley, Edward; Feltri, Maria Laura; Cox, Anderson O; Lee, Jingyun; Furdui, Cristina M; Liu, Liang; Bshara, Wiam; LaConte, Leslie EW; Kandel, Eugene S; Pasquale, Elena B; Qu, Jun; Hedstrom, Lizbeth; Nikiforov, Mikhail A
    Signal transduction pathways post-translationally regulating nucleotide metabolism remain largely unknown. Guanosine monophosphate reductase (GMPR) is a nucleotide metabolism enzyme that decreases GTP pools by converting GMP to IMP. We observed that phosphorylation of GMPR at Tyr267 is critical for its activity and found that this phosphorylation by ephrin receptor tyrosine kinase EPHA4 decreases GTP pools in cell protrusions and levels of GTP-bound RAC1. EPHs possess oncogenic and tumor-suppressor activities, although the mechanisms underlying switches between these two modes are poorly understood. We demonstrated that GMPR plays a key role in EPHA4-mediated RAC1 suppression. This supersedes GMPR-independent activation of RAC1 by EPHA4, resulting in a negative overall effect on melanoma cell invasion and tumorigenicity. Accordingly, EPHA4 levels increase during melanoma progression and inversely correlate with GMPR levels in individual melanoma tumors. Therefore, phosphorylation of GMPR at Tyr267 is a metabolic signal transduction switch controlling GTP biosynthesis and transformed phenotypes.
  • Thumbnail Image
    ItemOpen Access
    Regulation of local GTP availability controls RAC1 activity and cell invasion.
    (Nature communications, 2021-10) Bianchi-Smiraglia, Anna; Wolff, David W; Marston, Daniel J; Deng, Zhiyong; Han, Zhannan; Moparthy, Sudha; Wombacher, Rebecca M; Mussell, Ashley L; Shen, Shichen; Chen, Jialin; Yun, Dong-Hyun; O'Brien Cox, Anderson; Furdui, Cristina M; Hurley, Edward; Feltri, Maria Laura; Qu, Jun; Hollis, Thomas; Kengne, Jules Berlin Nde; Fongang, Bernard; Sousa, Rui J; Kandel, Mikhail E; Kandel, Eugene S; Hahn, Klaus M; Nikiforov, Mikhail A
    Physiological changes in GTP levels in live cells have never been considered a regulatory step of RAC1 activation because intracellular GTP concentration (determined by chromatography or mass spectrometry) was shown to be substantially higher than the in vitro RAC1 GTP dissociation constant (RAC1-GTP Kd). Here, by combining genetically encoded GTP biosensors and a RAC1 activity biosensor, we demonstrated that GTP levels fluctuating around RAC1-GTP Kd correlated with changes in RAC1 activity in live cells. Furthermore, RAC1 co-localized in protrusions of invading cells with several guanylate metabolism enzymes, including rate-limiting inosine monophosphate dehydrogenase 2 (IMPDH2), which was partially due to direct RAC1-IMPDH2 interaction. Substitution of endogenous IMPDH2 with IMPDH2 mutants incapable of binding RAC1 did not affect total intracellular GTP levels but suppressed RAC1 activity. Targeting IMPDH2 away from the plasma membrane did not alter total intracellular GTP pools but decreased GTP levels in cell protrusions, RAC1 activity, and cell invasion. These data provide a mechanism of regulation of RAC1 activity by local GTP pools in live cells.
  • Thumbnail Image
    ItemOpen Access
    The fatty acid elongase ELOVL6 regulates bortezomib resistance in multiple myeloma
    (Blood Advances, 2021-04-13) Lipchick, Brittany C; Utley, Adam; Han, Zhannan; Moparthy, Sudha; Yun, Dong Hyun; Bianchi-Smiraglia, Anna; Wolff, David W; Fink, Emily; Liu, Liang; Furdui, Cristina M; Lee, Jingyun; Lee, Kelvin P; Nikiforov, Mikhail A
    Abstract Resistance to the proteasome inhibitor bortezomib (BTZ) represents a major obstacle in the treatment of multiple myeloma (MM). The contribution of lipid metabolism in the resistance of MM cells to BTZ is mostly unknown. Here we report that levels of fatty acid elongase 6 (ELOVL6) were lower in MM cells from BTZ-nonresponsive vs BTZ-responsive patients and in cultured MM cells selected for BTZ resistance compared with parental counterparts. Accordingly, depletion of ELOVL6 in parental MM cells suppressed BTZ-induced endoplasmic reticulum (ER) stress and cytotoxicity, whereas restoration of ELOVL6 levels in BTZ-resistant MM cells sensitized them to BTZ in tissue culture settings and, as xenografts, in a plasmacytoma mouse model. Furthermore, for the first time, we identified changes in the BTZ-induced lipidome between parental and BTZ-resistant MM cell lines underlying a functional difference in their response to BTZ. We demonstrated that restoration of ELOVL6 levels in BTZ-resistant MM cells resensitized them to BTZ largely via upregulation of ELOVL6-dependent ceramide species, which was a prerequisite for BTZ-induced ER stress and cell death in these cells. Our data characterize ELOVL6 as a major clinically relevant regulator of MM cell resistance to BTZ, which can emerge from the impaired ability of these cells to alter ceramide composition in response to BTZ.
  • Thumbnail Image
    ItemOpen Access
    XBP1-KLF9 Axis Acts as a Molecular Rheostat to Control the Transition from Adaptive to Cytotoxic Unfolded Protein Response
    (Cell Reports, 2018-10) Fink, Emily E; Moparthy, Sudha; Bagati, Archis; Bianchi-Smiraglia, Anna; Lipchick, Brittany C; Wolff, David W; Roll, Matthew V; Wang, Jianmin; Liu, Song; Bakin, Andrei V; Kandel, Eugene S; Lee, Ann-Hwee; Nikiforov, Mikhail A