TY - JOUR

T1 - Mechanism of protein tyrosine phosphatase 1B-mediated inhibition of leptin signalling

AU - Lund, I K

AU - Hansen, J A

AU - Andersen, H S

AU - Møller, N P H

AU - Billestrup, Nils

PY - 2005/4/1

Y1 - 2005/4/1

N2 - Upon leptin binding, the leptin receptor is activated, leading to stimulation of the JAK/STAT signal transduction cascade. The transient character of the tyrosine phosphorylation of JAK2 and STAT3 suggests the involvement of protein tyrosine phosphatases (PTPs) as negative regulators of this signalling pathway. Specifically, recent evidence has suggested that PTP1B might be a key regulator of leptin signalling, based on the resistance to diet-induced obesity and increased leptin signalling observed in PTP1B-deficient mice. The present study was undertaken to investigate the mechanism by which PTP1B mediates the cessation of the leptin signal transduction. Leptin-induced activation of a STAT3 responsive reporter was dose-dependently inhibited by co-transfection with PTP1B. No inhibition was observed when a catalytically inactive mutant of PTP1B was used or when other PTPs were co-transfected. PTP1B was able to dephosphorylate activated JAK2 and STAT3 in vitro, whereas either no or a minimal effect was observed with cluster of differentiation 45 (CD45), PTPalpha and leukocyte antigen-related (LAR). By utilisation of a selective PTP1B inhibitor, the leptin-induced STAT3 activation was enhanced in cells. In conclusion, these results suggested that the negative regulatory role of PTP1B on leptin signalling is mediated through a direct and selective dephosphorylation of the two signalling molecules, JAK2 and STAT3.

AB - Upon leptin binding, the leptin receptor is activated, leading to stimulation of the JAK/STAT signal transduction cascade. The transient character of the tyrosine phosphorylation of JAK2 and STAT3 suggests the involvement of protein tyrosine phosphatases (PTPs) as negative regulators of this signalling pathway. Specifically, recent evidence has suggested that PTP1B might be a key regulator of leptin signalling, based on the resistance to diet-induced obesity and increased leptin signalling observed in PTP1B-deficient mice. The present study was undertaken to investigate the mechanism by which PTP1B mediates the cessation of the leptin signal transduction. Leptin-induced activation of a STAT3 responsive reporter was dose-dependently inhibited by co-transfection with PTP1B. No inhibition was observed when a catalytically inactive mutant of PTP1B was used or when other PTPs were co-transfected. PTP1B was able to dephosphorylate activated JAK2 and STAT3 in vitro, whereas either no or a minimal effect was observed with cluster of differentiation 45 (CD45), PTPalpha and leukocyte antigen-related (LAR). By utilisation of a selective PTP1B inhibitor, the leptin-induced STAT3 activation was enhanced in cells. In conclusion, these results suggested that the negative regulatory role of PTP1B on leptin signalling is mediated through a direct and selective dephosphorylation of the two signalling molecules, JAK2 and STAT3.

KW - Animals

KW - Cell Line

KW - Cricetinae

KW - DNA-Binding Proteins

KW - Enzyme Inhibitors

KW - Gene Expression Regulation

KW - Genes, Reporter

KW - Humans

KW - Janus Kinase 2

KW - Leptin

KW - Mice

KW - Molecular Structure

KW - Promoter Regions, Genetic

KW - Protein Tyrosine Phosphatase, Non-Receptor Type 1

KW - Protein Tyrosine Phosphatases

KW - Protein-Tyrosine Kinases

KW - Proto-Oncogene Proteins

KW - Receptors, Cell Surface

KW - Receptors, Leptin

KW - Recombinant Fusion Proteins

KW - STAT3 Transcription Factor

KW - Signal Transduction

KW - Trans-Activators

U2 - 10.1677/jme.1.01694

DO - 10.1677/jme.1.01694

M3 - Journal article

C2 - 15821101

VL - 34

SP - 339

EP - 351

JO - Journal of Molecular Endocrinology

JF - Journal of Molecular Endocrinology

SN - 0952-5041

IS - 2

ER -