Cellular effects of small molecule PTP1B inhibitors on insulin signaling.
Protein tyrosine phosphatase 1B (PTP1B) is implicated as a negative regulator of insulin receptor (IR) signaling and a potential drug target for the treatment of type 2 diabetes and other associated metabolic syndromes. To further define the role of PTP1B in insulin signaling and to test the hypothesis that blocking the activity of PTP1B would augment the action of insulin, we prepared several cell permeable, potent and selective, small molecule PTP1B inhibitors, and evaluated their biological effects in several insulin sensitive cell lines. Our data indicate that PTP1B inhibitors bind to and colocalize with PTP1B on the surface of the endoplasmic reticulum and PTP1B exerts its negative effect on insulin signaling upstream of phosphatidylinositol 3-kinase and MEK1. Treatment of cells with PTP1B inhibitors, both in the presence and in the absence of insulin, markedly enhances IRbeta and IRS-1 phosphorylation, Akt and ERK1/2 activation, Glut4 translocation, glucose uptake, and Elk1 transcriptional activation and cell proliferation. These results indicate that small molecule inhibitors targeted to PTP1B can act as both insulin mimetics and insulin sensitizers. Taken together, our findings combined with results from PTP1B knockout, antisense, and biochemical studies provide strong evidence that PTP1B negatively regulates insulin signaling and that small molecule PTP1B inhibitors have the ability to potentiate and augment the action of insulin.
Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
Laiping
L
Xie
Seung-Yub
SY
Lee
Jannik N
JN
Andersen
Steve
S
Waters
Kui
K
Shen
Xiao-Ling
XL
Guo
Niels Peter H
NP
Moller
Jerrold M
JM
Olefsky
David S
DS
Lawrence
Zhong-Yin
ZY
Zhang
D000818:Animals; D016466:CHO Cells; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D004268:DNA-Binding Proteins; D020536:Enzyme Activators / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D048369:MAP Kinase Kinase 1; D019950:Mitogen-Activated Protein Kinase 1 / Q000737:chemistry; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000737:chemistry; D020928:Mitogen-Activated Protein Kinases / Q000737:chemistry; D032446:Myoblasts / Q000187:drug effects / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry; D010750:Phosphoproteins / Q000737:chemistry; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors; D014443:Tyrosine / Q000378:metabolism; D050807:ets-Domain Protein Elk-1
D004268:DNA-Binding Proteins; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D005947:Glucose; D055504:Insulin Receptor Substrate Proteins; D048369:MAP Kinase Kinase 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin; D014157:Transcription Factors; D014443:Tyrosine; D050807:ets-Domain Protein Elk-1; C494112:ELK1 protein, human; C526292:IRS1 protein, human; C494918:AKT1 protein, human; C482125:MAP2K1 protein, human; C516607:PTPN1 protein, human