• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. Jun 1995; 95(6): 2806–2812.
PMCID: PMC295966

Increased abundance of the receptor-type protein-tyrosine phosphatase LAR accounts for the elevated insulin receptor dephosphorylating activity in adipose tissue of obese human subjects.


Protein-tyrosine phosphatases (PTPases) have an essential role in the regulation of the steady-state phosphorylation of the insulin receptor and other proteins in the insulin signalling pathway. To examine whether increased PTPase activity is associated with adipose tissue insulin resistance in human obesity we measured PTPase enzyme activity towards the insulin receptor in homogenates of subcutaneous adipose tissue from a series of six lean and six nondiabetic, obese (body mass index > 30) subjects. The obese subjects had a mean 1.74-fold increase in PTPase activity (P < 0.0001) with a striking positive correlation by linear regression analysis between PTPase activity and body mass index among all of the samples (R = 0.918; P < 0.0001). The abundance of three candidate insulin receptor PTPases in adipose tissue was also estimated by immunoblot analysis. The most prominent increase was a 2.03-fold rise in the transmembrane PTPase LAR (P < 0.001). Of the three PTPase examined, only immunodepletion of LAR protein from the homogenates with neutralizing antibodies resulted in normalization of the PTPase activity towards the insulin receptor, demonstrating that the increase in LAR was responsible for the enhanced PTPase activity in the adipose tissue from obese subjects. These studies suggest that increased PTPase activity towards the insulin receptor is a pathogenetic factor in the insulin resistance of adipose tissue in human obesity and provide evidence for a potential role of the LAR PTPase in the regulation of insulin signalling in disease states.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.6M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Rabinowitz D. Some endocrine and metabolic aspects of obesity. Annu Rev Med. 1970;21:241–258. [PubMed]
  • Kolterman OG, Insel J, Saekow M, Olefsky JM. Mechanisms of insulin resistance in human obesity: evidence for receptor and postreceptor defects. J Clin Invest. 1980 Jun;65(6):1272–1284. [PMC free article] [PubMed]
  • Caro JF, Dohm LG, Pories WJ, Sinha MK. Cellular alterations in liver, skeletal muscle, and adipose tissue responsible for insulin resistance in obesity and type II diabetes. Diabetes Metab Rev. 1989 Dec;5(8):665–689. [PubMed]
  • White MF, Kahn CR. The insulin signaling system. J Biol Chem. 1994 Jan 7;269(1):1–4. [PubMed]
  • Goldstein BJ. Regulation of insulin receptor signaling by protein-tyrosine dephosphorylation. Receptor. 1993 Spring;3(1):1–15. [PubMed]
  • Fischer EH, Charbonneau H, Tonks NK. Protein tyrosine phosphatases: a diverse family of intracellular and transmembrane enzymes. Science. 1991 Jul 26;253(5018):401–406. [PubMed]
  • Streuli M, Krueger NX, Hall LR, Schlossman SF, Saito H. A new member of the immunoglobulin superfamily that has a cytoplasmic region homologous to the leukocyte common antigen. J Exp Med. 1988 Nov 1;168(5):1523–1530. [PMC free article] [PubMed]
  • Chernoff J, Schievella AR, Jost CA, Erikson RL, Neel BG. Cloning of a cDNA for a major human protein-tyrosine-phosphatase. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2735–2739. [PMC free article] [PubMed]
  • Guan KL, Haun RS, Watson SJ, Geahlen RL, Dixon JE. Cloning and expression of a protein-tyrosine-phosphatase. Proc Natl Acad Sci U S A. 1990 Feb;87(4):1501–1505. [PMC free article] [PubMed]
  • Freeman RM, Jr, Plutzky J, Neel BG. Identification of a human src homology 2-containing protein-tyrosine-phosphatase: a putative homolog of Drosophila corkscrew. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11239–11243. [PMC free article] [PubMed]
  • Ahmad S, Banville D, Zhao Z, Fischer EH, Shen SH. A widely expressed human protein-tyrosine phosphatase containing src homology 2 domains. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2197–2201. [PMC free article] [PubMed]
  • Ding W, Zhang WR, Sullivan K, Hashimoto N, Goldstein BJ. Identification of protein-tyrosine phosphatases prevalent in adipocytes by molecular cloning. Biochem Biophys Res Commun. 1994 Jul 29;202(2):902–907. [PubMed]
  • Mooney RA, Anderson DL. Phosphorylation of the insulin receptor in permeabilized adipocytes is coupled to a rapid dephosphorylation reaction. J Biol Chem. 1989 Apr 25;264(12):6850–6857. [PubMed]
  • Bernier M, Liotta AS, Kole HK, Shock DD, Roth J. Dynamic regulation of intact and C-terminal truncated insulin receptor phosphorylation in permeabilized cells. Biochemistry. 1994 Apr 12;33(14):4343–4351. [PubMed]
  • Hashimoto N, Feener EP, Zhang WR, Goldstein BJ. Insulin receptor protein-tyrosine phosphatases. Leukocyte common antigen-related phosphatase rapidly deactivates the insulin receptor kinase by preferential dephosphorylation of the receptor regulatory domain. J Biol Chem. 1992 Jul 15;267(20):13811–13814. [PubMed]
  • Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. [PubMed]
  • Kasuga M, White MF, Kahn CR. Phosphorylation of the insulin receptor in cultured hepatoma cells and a solubilized system. Methods Enzymol. 1985;109:609–621. [PubMed]
  • Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. [PubMed]
  • Towbin H, Staehelin T, Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350–4354. [PMC free article] [PubMed]
  • Hashimoto N, Zhang WR, Goldstein BJ. Insulin receptor and epidermal growth factor receptor dephosphorylation by three major rat liver protein-tyrosine phosphatases expressed in a recombinant bacterial system. Biochem J. 1992 Jun 1;284(Pt 2):569–576. [PMC free article] [PubMed]
  • Milarski KL, Saltiel AR. Expression of catalytically inactive Syp phosphatase in 3T3 cells blocks stimulation of mitogen-activated protein kinase by insulin. J Biol Chem. 1994 Aug 19;269(33):21239–21243. [PubMed]
  • Xiao S, Rose DW, Sasaoka T, Maegawa H, Burke TR, Jr, Roller PP, Shoelson SE, Olefsky JM. Syp (SH-PTP2) is a positive mediator of growth factor-stimulated mitogenic signal transduction. J Biol Chem. 1994 Aug 19;269(33):21244–21248. [PubMed]
  • Caro JF. Clinical review 26: Insulin resistance in obese and nonobese man. J Clin Endocrinol Metab. 1991 Oct;73(4):691–695. [PubMed]
  • Campbell PJ, Gerich JE. Impact of obesity on insulin action in volunteers with normal glucose tolerance: demonstration of a threshold for the adverse effect of obesity. J Clin Endocrinol Metab. 1990 Apr;70(4):1114–1118. [PubMed]
  • Boden G, Chen X, DeSantis RA, Kendrick Z. Effects of age and body fat on insulin resistance in healthy men. Diabetes Care. 1993 May;16(5):728–733. [PubMed]
  • Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988 Dec;37(12):1595–1607. [PubMed]
  • Olefsky JM. Decreased insulin binding to adipocytes and circulating monocytes from obese subjects. J Clin Invest. 1976 May;57(5):1165–1172. [PMC free article] [PubMed]
  • Ciaraldi TP, Molina JM, Olefsky JM. Insulin action kinetics in adipocytes from obese and noninsulin-dependent diabetes mellitus subjects: identification of multiple cellular defects in glucose transport. J Clin Endocrinol Metab. 1991 Apr;72(4):876–882. [PubMed]
  • Freidenberg GR, Henry RR, Klein HH, Reichart DR, Olefsky JM. Decreased kinase activity of insulin receptors from adipocytes of non-insulin-dependent diabetic subjects. J Clin Invest. 1987 Jan;79(1):240–250. [PMC free article] [PubMed]
  • Takayama S, Kahn CR, Kubo K, Foley JE. Alterations in insulin receptor autophosphorylation in insulin resistance: correlation with altered sensitivity to glucose transport and antilipolysis to insulin. J Clin Endocrinol Metab. 1988 May;66(5):992–999. [PubMed]
  • Sinha MK, Pories WJ, Flickinger EG, Meelheim D, Caro JF. Insulin-receptor kinase activity of adipose tissue from morbidly obese humans with and without NIDDM. Diabetes. 1987 May;36(5):620–625. [PubMed]
  • Meyerovitch J, Rothenberg P, Shechter Y, Bonner-Weir S, Kahn CR. Vanadate normalizes hyperglycemia in two mouse models of non-insulin-dependent diabetes mellitus. J Clin Invest. 1991 Apr;87(4):1286–1294. [PMC free article] [PubMed]
  • Posner BI, Faure R, Burgess JW, Bevan AP, Lachance D, Zhang-Sun G, Fantus IG, Ng JB, Hall DA, Lum BS, et al. Peroxovanadium compounds. A new class of potent phosphotyrosine phosphatase inhibitors which are insulin mimetics. J Biol Chem. 1994 Feb 11;269(6):4596–4604. [PubMed]
  • Shisheva A, Ikonomov O, Shechter Y. The protein tyrosine phosphatase inhibitor, pervanadate, is a powerful antidiabetic agent in streptozotocin-treated diabetic rats. Endocrinology. 1994 Jan;134(1):507–510. [PubMed]
  • Meyerovitch J, Backer JM, Kahn CR. Hepatic phosphotyrosine phosphatase activity and its alterations in diabetic rats. J Clin Invest. 1989 Sep;84(3):976–983. [PMC free article] [PubMed]
  • Begum N, Sussman KE, Draznin B. Differential effects of diabetes on adipocyte and liver phosphotyrosine and phosphoserine phosphatase activities. Diabetes. 1991 Dec;40(12):1620–1629. [PubMed]
  • Boylan JM, Brautigan DL, Madden J, Raven T, Ellis L, Gruppuso PA. Differential regulation of multiple hepatic protein tyrosine phosphatases in alloxan diabetic rats. J Clin Invest. 1992 Jul;90(1):174–179. [PMC free article] [PubMed]
  • Goren HJ, Boland D. The 180000 molecular weight plasma membrane insulin receptor substrate is a protein tyrosine phosphatase and is elevated in diabetic plasma membranes. Biochem Biophys Res Commun. 1991 Oct 31;180(2):463–469. [PubMed]
  • Nadiv O, Shinitzky M, Manu H, Hecht D, Roberts CT, Jr, LeRoith D, Zick Y. Elevated protein tyrosine phosphatase activity and increased membrane viscosity are associated with impaired activation of the insulin receptor kinase in old rats. Biochem J. 1994 Mar 1;298(Pt 2):443–450. [PMC free article] [PubMed]
  • McGuire MC, Fields RM, Nyomba BL, Raz I, Bogardus C, Tonks NK, Sommercorn J. Abnormal regulation of protein tyrosine phosphatase activities in skeletal muscle of insulin-resistant humans. Diabetes. 1991 Jul;40(7):939–942. [PubMed]
  • Kusari J, Kenner KA, Suh KI, Hill DE, Henry RR. Skeletal muscle protein tyrosine phosphatase activity and tyrosine phosphatase 1B protein content are associated with insulin action and resistance. J Clin Invest. 1994 Mar;93(3):1156–1162. [PMC free article] [PubMed]
  • Kulas DT, Zhang WR, Goldstein BJ, Furlanetto RW, Mooney RA. Insulin receptor signaling is augmented by antisense inhibition of the protein tyrosine phosphatase LAR. J Biol Chem. 1995 Feb 10;270(6):2435–2438. [PubMed]
  • Charbonneau H, Tonks NK, Kumar S, Diltz CD, Harrylock M, Cool DE, Krebs EG, Fischer EH, Walsh KA. Human placenta protein-tyrosine-phosphatase: amino acid sequence and relationship to a family of receptor-like proteins. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5252–5256. [PMC free article] [PubMed]
  • Lammers R, Bossenmaier B, Cool DE, Tonks NK, Schlessinger J, Fischer EH, Ullrich A. Differential activities of protein tyrosine phosphatases in intact cells. J Biol Chem. 1993 Oct 25;268(30):22456–22462. [PubMed]
  • Sun XJ, Crimmins DL, Myers MG, Jr, Miralpeix M, White MF. Pleiotropic insulin signals are engaged by multisite phosphorylation of IRS-1. Mol Cell Biol. 1993 Dec;13(12):7418–7428. [PMC free article] [PubMed]
  • Kuhné MR, Pawson T, Lienhard GE, Feng GS. The insulin receptor substrate 1 associates with the SH2-containing phosphotyrosine phosphatase Syp. J Biol Chem. 1993 Jun 5;268(16):11479–11481. [PubMed]
  • Sugimoto S, Wandless TJ, Shoelson SE, Neel BG, Walsh CT. Activation of the SH2-containing protein tyrosine phosphatase, SH-PTP2, by phosphotyrosine-containing peptides derived from insulin receptor substrate-1. J Biol Chem. 1994 May 6;269(18):13614–13622. [PubMed]
  • Maegawa H, Ugi S, Ishibashi O, Tachikawa-Ide R, Takahara N, Tanaka Y, Takagi Y, Kikkawa R, Shigeta Y, Kashiwagi A. Src homology 2 domains of protein tyrosine phosphatase are phosphorylated by insulin receptor kinase and bind to the COOH-terminus of insulin receptors in vitro. Biochem Biophys Res Commun. 1993 Jul 15;194(1):208–214. [PubMed]
  • Maegawa H, Ugi S, Adachi M, Hinoda Y, Kikkawa R, Yachi A, Shigeta Y, Kashiwagi A. Insulin receptor kinase phosphorylates protein tyrosine phosphatase containing Src homology 2 regions and modulates its PTPase activity in vitro. Biochem Biophys Res Commun. 1994 Mar 15;199(2):780–785. [PubMed]
  • Ugi S, Maegawa H, Olefsky JM, Shigeta Y, Kashiwagi A. Src homology 2 domains of protein tyrosine phosphatase are associated in vitro with both the insulin receptor and insulin receptor substrate-1 via different phosphotyrosine motifs. FEBS Lett. 1994 Mar 7;340(3):216–220. [PubMed]
  • Vogel W, Lammers R, Huang J, Ullrich A. Activation of a phosphotyrosine phosphatase by tyrosine phosphorylation. Science. 1993 Mar 12;259(5101):1611–1614. [PubMed]
  • Kuhné MR, Zhao Z, Rowles J, Lavan BE, Shen SH, Fischer EH, Lienhard GE. Dephosphorylation of insulin receptor substrate 1 by the tyrosine phosphatase PTP2C. J Biol Chem. 1994 Jun 3;269(22):15833–15837. [PubMed]
  • Streuli M, Krueger NX, Ariniello PD, Tang M, Munro JM, Blattler WA, Adler DA, Disteche CM, Saito H. Expression of the receptor-linked protein tyrosine phosphatase LAR: proteolytic cleavage and shedding of the CAM-like extracellular region. EMBO J. 1992 Mar;11(3):897–907. [PMC free article] [PubMed]
  • Yu Q, Lenardo T, Weinberg RA. The N-terminal and C-terminal domains of a receptor tyrosine phosphatase are associated by non-covalent linkage. Oncogene. 1992 Jun;7(6):1051–1057. [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...