title: Differentiation-dependent suppression of platelet-derived growth factor signaling in cultured adipocytes.
abstract: A critical component of vertebrate cellular differentiation is the acquisition of sensitivity to a restricted subset of peptide hormones and growth factors. This accounts for the unique capability of insulin (and possibly insulin-like growth factor-1), but not other growth factors, to stimulate glucose uptake and anabolic metabolism in heart, skeletal muscle, and adipose tissue. This selectivity is faithfully recapitulated in the cultured adipocyte line, 3T3-L1, which responds to insulin, but not platelet-derived growth factor (PDGF), with increased hexose uptake. The serine/threonine protein kinases Akt1 and Akt2, which have been implicated as mediators of insulin-stimulated glucose uptake, as well as glycogen, lipid, and protein synthesis, were shown to mirror this selectivity in this tissue culture system. This was particularly apparent in 3T3-L1 adipocytes overexpressing an epitope-tagged form of Akt2 in which insulin activated Akt2 10-fold better than PDGF. Similarly, in 3T3-L1 adipocytes, only insulin stimulated phosphorylation of Akt's endogenous substrate, GSK-3beta. Other signaling molecules, including phosphatidylinositol 3-kinase, pp70 S6-kinase, mitogen-activated protein kinase, and PHAS-1/4EBP-1, did not demonstrate this selective responsiveness to insulin but were instead activated comparably by both insulin and PDGF. Moreover, concurrent treatment with PDGF and insulin did not diminish activation of phosphatidylinositol 3-kinase, Akt, or glucose transport, indicating that PDGF did not simultaneously activate an inhibitory mechanism. Interestingly, PDGF and insulin comparably stimulated both Akt isoforms, as well as numerous other signaling molecules, in undifferentiated 3T3-L1 preadipocytes. Collectively, these data suggest that differential activation of Akt in adipocytes may contribute to insulin's exclusive mediation of the metabolic events involved in glucose metabolism. Moreover, they suggest a novel mechanism by which differentiation-dependent hormone selectivity is conferred through the suppression of specific signaling pathways operational in undifferentiated cell types.
authors.affiliation: Howard Hughes Medical Institute, The Cox Institute, University of Pennsylvania Medical School, Philadelphia, Pennsylvania 19104, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Summers
authors.forename: E L
authors.initials: EL
authors.lastname: Whiteman
authors.forename: H
authors.initials: H
authors.lastname: Cho
authors.forename: L
authors.initials: L
authors.lastname: Lipfert
authors.forename: M J
authors.initials: MJ
authors.lastname: Birnbaum
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D002454:Cell Differentiation; D051275:Glucose Transporter Type 4; D038362:Glycogen Synthase Kinase 3; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D009004:Monosaccharide Transport Proteins / Q000502:physiology; D009124:Muscle Proteins; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D017479:Receptors, Platelet-Derived Growth Factor / Q000502:physiology
chemical_list: D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; C495692:SLC2A4 protein, human; C495693:Slc2a4 protein, mouse; D017479:Receptors, Platelet-Derived Growth Factor; C494918:AKT1 protein, human; C494921:AKT2 protein, human; C494922:Akt2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3