Endothelial pyruvate kinase M2 maintains vascular integrity.

The Journal of Clinical Investigation
Boa KimZolt Arany

Abstract

The M2 isoform of pyruvate kinase (PKM2) is highly expressed in most cancer cells, and has been studied extensively as a driver of oncogenic metabolism. In contrast, the role of PKM2 in nontransformed cells is little studied, and nearly nothing is known of its role, if any, in quiescent cells. We show here that endothelial cells express PKM2 almost exclusively over PKM1. In proliferating endothelial cells, PKM2 is required to suppress p53 and maintain cell cycle progression. In sharp contrast, PKM2 has a strikingly different role in quiescent endothelial cells, where inhibition of PKM2 leads to degeneration of tight junctions and barrier function. Mechanistically, PKM2 regulates barrier function independently of its canonical activity as a pyruvate kinase. Instead, PKM2 suppresses NF-kB and its downstream target, the vascular permeability factor angiopoietin 2. As a consequence, loss of endothelial cell PKM2 in vivo predisposes mice to VEGF-induced vascular leak, and to severe bacteremia and death in response to sepsis. Together, these data demonstrate new roles of PKM2 in quiescent cells, and highlight the need for caution in developing cancer therapies that target PKM2.

References

Oct 1, 1976·The American Journal of Anatomy·M M Sholley, R S Cotran
Feb 1, 1996·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·W K Kaufmann, R S Paules
Jul 6, 2005·Biochemistry·Jill D DombrauckasAndrew D Mesecar
Jul 12, 2008·Histochemistry and Cell Biology·Reinhold G ErbenSonja Rohleder
Sep 25, 2009·Nature Reviews. Cancer·Arnold J Levine, Moshe Oren
Jan 13, 2010·Cold Spring Harbor Perspectives in Biology·Jack T Zilfou, Scott W Lowe
Feb 17, 2010·The International Journal of Biochemistry & Cell Biology·Sybille Mazurek
Sep 18, 2010·Science·Matthew G Vander HeidenLewis C Cantley
Oct 13, 2010·Proceedings of the National Academy of Sciences of the United States of America·Nikolina DioufaHippokratis Kiaris
Dec 24, 2011·Nature Protocols·Marianne BakerKairbaan Hodivala-Dilke
Jan 25, 2012·The Journal of Experimental Medicine·Michael S Goldberg, Phillip A Sharp
Aug 28, 2012·Nature Chemical Biology·Dimitrios AnastasiouMatthew G Vander Heiden
Mar 26, 2013·Journal of Visualized Experiments : JoVE·Maria Radu, Jonathan Chernoff
Aug 6, 2013·Cell·Katrien De BockPeter Carmeliet
Apr 22, 2014·Journal of Visualized Experiments : JoVE·Robert SzulcekGeerten P van Nieuw Amerongen
Jul 31, 2014·Nature Methods·Neville E SanjanaFeng Zhang
Dec 9, 2014·Molecular Cell·Sophia Y LuntMatthew G Vander Heiden
Mar 5, 2015·Biochemical and Biophysical Research Communications·Meredith L ReesHeinrich Taegtmeyer
Apr 22, 2016·Science Translational Medicine·Sangyeul HanGou Young Koh
May 21, 2016·Arteriosclerosis, Thrombosis, and Vascular Biology·Jes-Niels BoeckelStefanie Dimmeler
Nov 20, 2016·EMBO Reports·Talya L DaytonMatthew G Vander Heiden
May 4, 2017·Journal of the American Society of Nephrology : JASN·Samir M Parikh
May 4, 2017·Nature·Pengchun YuMichael Simons
Nov 21, 2017·Trends in Cell Biology·Katerina RohlenovaPeter Carmeliet
Feb 8, 2018·Cell Metabolism·Xinshou OuyangWajahat Zafar Mehal
Apr 14, 2018·Physiological Genomics·Allison Lesher WilliamsRalph V Shohet

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Citations

Jul 23, 2019·The EMBO Journal·Mauro SiragusaIngrid Fleming
Oct 28, 2019·Bioscience Reports·Ting TaoXiaoping Yang
May 28, 2020·International Journal of Molecular Sciences·Khalia R PrimerChristina A Bursill
Jul 23, 2020·Nature Metabolism·Kim D FalkenbergPeter Carmeliet
Oct 23, 2019·Scientific Reports·Jesús Gómez-EscuderoAlicia G Arroyo
Aug 25, 2020·Circulation Research·Guy EelenPeter Carmeliet
Mar 11, 2019·Vascular Biology·Tatiane Gorski, Katrien De Bock
Oct 23, 2020·Arteriosclerosis, Thrombosis, and Vascular Biology·Yunling Gao, Zorina S Galis
Feb 11, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Athanasios ZiogasDavid Sprott
Apr 3, 2021·Nature Cell Biology·Jorge AndradeMichael Potente
Nov 2, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Jing GaoWeili Shen
Apr 27, 2021·Antioxidants & Redox Signaling·Masuko Ushio-FukaiTohru Fukai
May 14, 2021·IScience·Swayam Prakash SrivastavaDaisuke Koya
Jun 2, 2021·Angiogenesis·Alessandra PasutPeter Carmeliet
Jun 24, 2021·American Journal of Physiology. Lung Cellular and Molecular Physiology·Reece P StevensJi Young Lee
Jul 10, 2021·NMR in Biomedicine·Lotte Bonde BertelsenChristoffer Laustsen
Jul 27, 2021·Journal of Cellular Physiology·Yoon-Beom LeeJae-Bong Park

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Methods Mentioned

BETA
xenograft
transfection
protein assay
flow cytometry
biopsy
PCR
ELISA

Software Mentioned

Image J

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