title: Biologically active leptin-related synthetic peptides activate STAT3 via phosphorylation of ERK1/2 and PI-3K.
abstract: The effects of leptin-related synthetic peptides [d-Leu-4]-OB3 and OB3 on energy balance and glucose homeostasis in ob/ob and db/db mice have been confirmed. The molecular basis of these effects, however, remains unclear. In the present study, we examined the ability of these peptides to activate signal transduction pathways known to be involved in transduction of the leptin signal. In a specific and concentration-dependent manner, [d-Leu-4]-OB3 induced phosphorylation of ERK1/2, PI-3K, Ser-727 STAT3, and Tyr-705 of STAT3. OB3 also induced activation of STAT3 via phosphorylation of ERK1/2, STAT3 Ser-727, STAT3 Tyr-705 and PI-3K p85, but to a lesser degree. Using PD98059 and LY294002, specific inhibitors of MEK and PI-3K, respectively, we were able to identify the signal transduction pathways involved in peptide-induced STAT3 activation. [d-Leu-4]-OB3 induced serine phosphorylation of STAT3 primarily through activation of ERK1/2. Tyrosine phosphorylation of STAT3, however, was induced primarily through activation of PI-3K. Our data suggest that in db/db mice, [d-Leu-4]-OB3 binding to short isoforms of the leptin receptor induces intracellular signaling cascades which do not require OB-Rb activation. These signals may ultimately result in peptide effects on transcriptional and translational events associated with energy balance and glycemic regulation. In summary, we have shown for the first time that, similar to leptin, bioactive leptin-related synthetic peptide analogs activate STAT3 via phosphorylation of serine and tyrosine residues by multiple signal transduction pathways.
authors.affiliation: Taipei Cancer Center, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hung-Yun
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Sheng-Huei
authors.initials: SH
authors.lastname: Yang
authors.affiliation: Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA.
authors.forename: Heng-Yuan
authors.initials: HY
authors.lastname: Tang
authors.affiliation: Taipei Cancer Center, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Guei-Yun
authors.initials: GY
authors.lastname: Cheng
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Davis
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, Albany Medical College, Albany, NY 12208, USA. Electronic address: grassop@mail.amc.edu.
authors.forename: Patricia
authors.initials: P
authors.lastname: Grasso
mesh_terms: D000818:Animals; D020738:Leptin / Q000138:chemical synthesis / Q000737:chemistry / Q000235:genetics*; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014443:Tyrosine
chemical_list: D020738:Leptin; D010455:Peptides; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014443:Tyrosine; D012694:Serine; D019869:Phosphatidylinositol 3-Kinases; D048052:Mitogen-Activated Protein Kinase 3
keywords: Leptin; Mitogen-activated protein kinase (MAPK); Phosphatidylinositol 3-kinase (PI-3K); Signal transducer and activator of transduction-3 (STAT3)