title: Human biliverdin reductase-based peptides activate and inhibit glucose uptake through direct interaction with the kinase domain of insulin receptor.
abstract: Insulin binding changes conformation of the insulin receptor kinase (IRK) domain and initiates glucose uptake through the insulin, IGF-1, phosphatidyl inositol 3-kinase (PI3K), and MAPK pathways; human biliverdin reductase (hBVR) is an IRK substrate and pathway effector. This is the first report on hBVR peptide-mediated IRK activation and conformational change. (290)KYCCSRK, which increased IRK V(max) without changing K(m), stimulated glucose uptake and potentiated insulin and IGF-1 stimulation in 4 cell lines. KYCCSRK in native hBVR was necessary for the hBVR and IRK cross-activation. Peptide treatment also activated PI3K downstream effectors, Akt and ERK, phosphorylation, and Elk transcriptional activity. In cells transfected with CMV-regulated EGFP-VP-peptide plasmid, C(292)→A mutant did not stimulate glucose uptake; K(296)→A decreased uptake and kinase activity. KEDQYMKMTV, corresponding to hBVR's SH2-binding domain, was a potent inhibitor of glucose uptake and IRK. The mechanism of action of peptides was examined using cells expressing IRK (aa 988-1263) activated by coexpressed KYCCSRK. Three active cys-mutants of IRK, with fluorophore coupled to cysteines, C(1056), C(1138), or C(1234), were examined for changes in fluorescence emission spectra in the presence of peptides. KYCCSRK and KEDQYMKMTV bound to different sites in IRK. The findings identify novel agents for activating or inhibiting insulin signaling and offer a new approach for treatment of type 2 diabetes and hypoglycemia.
authors.affiliation: Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Peter E M
authors.initials: PE
authors.lastname: Gibbs
authors.affiliation: Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Lerner-Marmarosh
authors.affiliation: Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Amelia
authors.initials: A
authors.lastname: Poulin
authors.affiliation: Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Elie
authors.initials: E
authors.lastname: Farah
authors.affiliation: Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA mahin_maines@urmc.rochester.edu.
authors.forename: Mahin D
authors.initials: MD
authors.lastname: Maines
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011487:Protein Conformation / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D015703:Antigens, CD; D010446:Peptide Fragments; D007334:Insulin-Like Growth Factor I; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase; D019869:Phosphatidylinositol 3-Kinases; C435941:INSR protein, human; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D005947:Glucose
keywords: diabetes; heme metabolism; protein kinases