title: Platelet-derived growth factor (PDGF) stimulates glucose transport in 3T3-L1 adipocytes overexpressing PDGF receptor by a pathway independent of insulin receptor substrates.
abstract: Insulin is unique among growth factors and hormones in its ability to control metabolic functions such as the stimulation of glucose uptake and glucose transporter (GLUT4) translocation in physiological target tissues, such as muscle and adipose cells. Nonetheless, the mechanisms underlying this specificity have remained incompletely understood, particularly in view of the ability of some growth factors to mimic insulin-dependent early signaling events. In this study, we have probed the basis of insulin specificity by overexpressing in hormone-responsive 3T3-L1 adipocytes wild-type platelet-derived growth factor (PDGF) receptor (PDGFR)-beta and selected, informative mutant receptor proteins. We show that such adipocytes overexpressing wild-type PDGFR on exposure to cognate growth factor activate glucose transport, GLUT4 translocation, and the serine-threonine protein kinase Akt/protein kinase B to a degree comparable with that produced in response to insulin. In addition, PDGF elicits the robust generation of phosphatidylinositol-3,4,5-trisphosphate in vivo in PDGFR-overexpressing 3T3-L1 adipocytes. Expression of PDGFR-beta mutant proteins demonstrates that these responses require the presence of an intact phosphatidylinositol 3-kinase (PI3K)-binding site on the overexpressed PDGF receptor. Furthermore, PDGF stimulates these effects independent of insulin receptor substrate(IRS)-1 or IRS-2 tyrosine phosphorylation or docking to activated PI3K. These data demonstrate that 1) the basis of insulin-specific glucose transport in cultured adipocytes is the low level of receptors for other growth factors and 2) in the presence of adequate receptors, PDGF is fully capable of activating glucose transport in a manner requiring PI3K and subsequent phosphatidylinositol-3,4,5-trisphosphate accumulation but independent of insulin, insulin receptor, and IRS proteins.
authors.affiliation: Howard Hughes Medical Institute, Cox Institute, Cell and Molecular Biology Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Eileen L
authors.initials: EL
authors.lastname: Whiteman
authors.forename: Janine J
authors.initials: JJ
authors.lastname: Chen
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Birnbaum
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D015870:Gene Expression / Q000502:physiology; D005947:Glucose / Q000493:pharmacokinetics*; D051275:Glucose Transporter Type 4; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D050721:Proto-Oncogene Proteins c-cbl; D011972:Receptor, Insulin / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D044767:Ubiquitin-Protein Ligases
chemical_list: D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D018129:Phosphatidylinositol Phosphates; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; C495692:SLC2A4 protein, human; C495693:Slc2a4 protein, mouse; C060974:phosphatidylinositol 3,4,5-triphosphate; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D011972:Receptor, Insulin; D020797:Receptor, Platelet-Derived Growth Factor beta; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C067419:CBL protein, human; C493849:Cbl protein, mouse; D005947:Glucose