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- Title
Human biliverdin reductase-based peptides activate and inhibit glucose uptake through direct interaction with the kinase domain of insulin receptor.
- Authors
Gibbs, Peter E. M.; Lemer-Marmarosh, Nicole; Poulin, Amelia; Farah, Elie; Maines, Mahin D.
- 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. 290KYCCSRK, which increased IRK Vmax without changing Km, 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 P13K downstream effectors, Akt and ERK, phosphorylation, and Elk transcriptional activity. In cells transfected with CMV-regulated EGFP-VP-peptide plasmid, C292 → A mutant did not stimulate glucose uptake; K296 →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 cysmutants of IRK, with fluorophore coupled to cysteines, C1056 C1138, or C1234, were examined for changes in fluorescence emission spectra in the presence of peptides. KYCCSRK and KEDQ FMKMTV 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.
- Subjects
PROTEIN binding; INSULIN receptors; MITOGEN-activated protein kinase genetics; PEPTIDES; GLUCOSE; TYPE 2 diabetes
- Publication
FASEB Journal, 2014, Vol 28, Issue 6, p2478
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.13-247015