title: Protein tyrosine phosphatase 1B regulates pyruvate kinase M2 tyrosine phosphorylation.
abstract: Protein-tyrosine phosphatase 1B (PTP1B) is a physiological regulator of glucose homeostasis and adiposity and is a drug target for the treatment of obesity and diabetes. Here we identify pyruvate kinase M2 (PKM2) as a novel PTP1B substrate in adipocytes. PTP1B deficiency leads to increased PKM2 total tyrosine and Tyr(105) phosphorylation in cultured adipocytes and in vivo. Substrate trapping and mutagenesis studies identify PKM2 Tyr-105 and Tyr-148 as key sites that mediate PTP1B-PKM2 interaction. In addition, in vitro analyses illustrate a direct effect of Tyr-105 phosphorylation on PKM2 activity in adipocytes. Importantly, PTP1B pharmacological inhibition increased PKM2 Tyr-105 phosphorylation and decreased PKM2 activity. Moreover, PKM2 Tyr-105 phosphorylation is regulated nutritionally, decreasing in adipose tissue depots after high-fat feeding. Further, decreased PKM2 Tyr-105 phosphorylation correlates with the development of glucose intolerance and insulin resistance in rodents, non-human primates, and humans. Together, these findings identify PKM2 as a novel substrate of PTP1B and provide new insights into the regulation of adipose PKM2 activity.
authors: Nutrition Department, University of California Davis, Davis, California 95616, USA.
authors: Ahmed
authors: A
authors: Bettaieb
authors: Jesse
authors: J
authors: Bakke
authors: Naoto
authors: N
authors: Nagata
authors: Kosuke
authors: K
authors: Matsuo
authors: Yannan
authors: Y
authors: Xi
authors: Siming
authors: S
authors: Liu
authors: Daniel
authors: D
authors: AbouBechara
authors: Ramzi
authors: R
authors: Melhem
authors: Kimber
authors: K
authors: Stanhope
authors: Bethany
authors: B
authors: Cummings
authors: James
authors: J
authors: Graham
authors: Andrew
authors: A
authors: Bremer
authors: Sheng
authors: S
authors: Zhang
authors: Costas A
authors: CA
authors: Lyssiotis
authors: Zhong-Yin
authors: ZY
authors: Zhang
authors: Lewis C
authors: LC
authors: Cantley
authors: Peter J
authors: PJ
authors: Havel
authors: Fawaz G
authors: FG
authors: Haj
mesh_terms: D041721:3T3-L1 Cells; D002001:Adipose Tissue, Brown / Q000201:enzymology; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D000818:Animals; D059305:Diet, High-Fat; D004734:Energy Metabolism; D055785:Gene Knockdown Techniques; D018149:Glucose Intolerance; D006801:Humans; D007333:Insulin Resistance; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011770:Pyruvate Kinase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D019000:Phosphotyrosine; D011770:Pyruvate Kinase; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1
keywords: Adipocyte; Diabetes; Metabolism; Pyruvate Kinase; Signal Transduction; Tyrosine Protein Phosphatase (Tyrosine Phosphatase)
references: Nat Rev Drug Discov. 2002 Sep;1(9):696-709
references: 12209150
references: Sci Signal. 2009 Nov 17;2(97):ra73
references: 19920251
references: Genes Dev. 2008 May 15;22(10):1269-75
references: 18483216
references: Mol Cell Biol. 2000 Aug;20(15):5479-89
references: 10891488
references: Chem Biol Interact. 2008 Jul 10;174(1):69-78
references: 18534569
references: PLoS One. 2012;7(5):e36633
references: 22655028
references: Transgenic Res. 2006 Oct;15(5):647-53
references: 16952017
references: J Cell Biol. 1992 Apr;117(2):401-14
references: 1373143
references: J Clin Invest. 2009 May;119(5):1322-34
references: 19381015
references: J Biol Chem. 2011 Mar 18;286(11):9225-35
references: 21216966
references: Arch Biochem Biophys. 1973 Nov;159(1):292-6
references: 4784462
references: J Biol Chem. 1997 Jan 10;272(2):843-51
references: 8995372
references: J Biol Chem. 2007 Jun 15;282(24):17706-11
references: 17446165
references: Am J Physiol Regul Integr Comp Physiol. 2008 Dec;295(6):R1782-93
references: 18832086
references: Nature. 2008 Mar 13;452(7184):230-3
references: 18337823
references: PLoS One. 2012;7(4):e34412
references: 22509299
references: Sci Signal. 2011 Dec 13;4(203):ra86
references: 22169477
references: Nat Rev Mol Cell Biol. 2006 Nov;7(11):833-46
references: 17057753
references: Nature. 2008 Mar 13;452(7184):181-6
references: 18337815
references: Diabetes. 2002 Aug;51(8):2405-11
references: 12145151
references: Nat Chem Biol. 2012 Oct;8(10):839-47
references: 22922757
references: J Biol Chem. 2005 Apr 15;280(15):15038-46
references: 15699041
references: Nature. 2011 Dec 1;480(7375):118-22
references: 22056988
references: Proc Natl Acad Sci U S A. 2011 Aug 30;108(35):14670-5
references: 21873226
references: Curr Top Med Chem. 2003;3(7):749-57
references: 12678842
references: Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11357-62
references: 12169659
references: Biochemistry. 1994 Mar 1;33(8):2285-90
references: 7509638
references: Mol Cell. 2011 Jun 24;42(6):713-4
references: 21700216
references: PLoS One. 2012;7(2):e32700
references: 22389718
references: Clin Transl Sci. 2011 Aug;4(4):243-52
references: 21884510
references: Science. 2011 Dec 2;334(6060):1278-83
references: 22052977
references: Nature. 1998 Oct 22;395(6704):763-70
references: 9796811
references: Nat Rev Mol Cell Biol. 2006 Feb;7(2):85-96
references: 16493415
references: Endocrinology. 2009 Apr;150(4):1670-9
references: 19164474
references: Physiol Rev. 2004 Apr;84(2):623-47
references: 15044684
references: Cell. 2011 May 27;145(5):732-44
references: 21620138
references: Nat Med. 2006 Aug;12(8):917-24
references: 16845389
references: Structure. 1998 Feb 15;6(2):195-210
references: 9519410
references: J Med Chem. 2010 Feb 11;53(3):1048-55
references: 20017496
references: Nat Med. 2001 Jun;7(6):699-705
references: 11385507
references: Int J Biochem Cell Biol. 2008;40(5):1043-54
references: 18191611
references: Diabetes. 2009 Mar;58(3):590-9
references: 19074988
references: Biochemistry. 2003 Nov 11;42(44):12792-804
references: 14596593
references: Cell. 1992 Feb 7;68(3):545-60
references: 1739967
references: Nature. 1994 Dec 1;372(6505):425-32
references: 7984236
references: Mol Cell Biol. 2007 Nov;27(21):7727-34
references: 17724080
references: Biochem Biophys Res Commun. 1999 Mar 16;256(2):257-62
references: 10079172
references: Bioorg Med Chem Lett. 2010 Jun 1;20(11):3387-93
references: 20451379
references: J Biol Chem. 2008 Jun 6;283(23):15740-6
references: 18387954
references: Science. 2002 Mar 1;295(5560):1708-11
references: 11872838
references: Science. 1999 Mar 5;283(5407):1544-8
references: 10066179
references: Cell. 2004 Jan 23;116(2):337-50
references: 14744442
references: PLoS One. 2011 Jan 31;6(1):e16446
references: 21305007
references: Nature. 2006 Dec 14;444(7121):847-53
references: 17167472
references: Cell Signal. 2010 Apr;22(4):645-59
references: 20026400
references: Int J Cancer. 2008 Jul 15;123(2):312-321
references: 18425820
references: Cell Metab. 2010 Apr 7;11(4):248-52
references: 20374955
references: J Biol Chem. 2003 Jan 10;278(2):739-44
references: 12424235
references: Curr Protoc Mol Biol. 2012 Apr;Chapter 18:Unit18.19.1-27
references: 22470061
references: Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1680-5
references: 9050838
references: J Exp Med. 2012 Feb 13;209(2):217-24
references: 22271574
references: Lancet. 2002 Sep 7;360(9335):783-9
references: 12241840