Vanadate regulates the insulin mitogenic effect by modulating SHP-2 association with insulin receptor substrate 1 in JAr human choriocarcinoma cells.
Maternal hyperglycemia alters placental glucose metabolism and induces placental hypercellularity. In this study we investigated, in JAr cells, the effect of a protein tyrosine phosphatase inhibitor, vanadate, on the insulin receptor substrate 1 (IRS1)-mitogen-activated protein kinase (MAPK) pathway and on cell proliferation in the presence of normal or high glucose concentration. When JAr cells were cultured in the presence of 25 mmol/l glucose, treatment with vanadate completely prevented SHP-2 association with IRS1. However, vanadate treatment reverted the effect of high glucose on basal and insulin-stimulated insulin receptor and IRS1 phosphorylation. Similar effects were observed on MAPK activation. These events determined a related modification in cell proliferation. Indeed, after high glucose and vanadate treatment, thymidine incorporation levels were comparable to those observed in the presence of normal glucose concentration and in the absence of vanadate. Therefore, in JAr cells, vanadate exerts an inhibitory effect on cell proliferation. This action is related to a modulation of the SHP-2 association with IRS1 that in turn might regulate the phosphorylation state of the main substrates involved in mitogenesic signaling of the insulin receptor.
Bifulco
G
G
Department of Gynecology, Obstetrics and Physiology of Human Reproduction, Università degli Studi di Napoli Federico II, Via Pansini 5, 80131 Naples, Italy.
Caruso
M
M
Di Carlo
C
C
Acunzo
G
G
Votino
C
C
Pellicano
M
M
Beguinot
F
F
Nappi
C
C
D002455:Cell Division / Q000187:drug effects*; D002822:Choriocarcinoma; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005947:Glucose / Q000008:administration & dosage; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D010920:Placenta / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms; D014638:Vanadates / Q000494:pharmacology*
C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D014638:Vanadates; D020928:Mitogen-Activated Protein Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; D005947:Glucose