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Human biliverdin reductase‐based peptides activate and inhibit glucose uptake through direct interaction with the kinase domain of insulin receptor
Author(s) -
Gibbs Peter E. M.,
LernerMarmarosh Nicole,
Poulin Amelia,
Farah Elie,
Maines Mahin D.
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-247015
Subject(s) - microbiology and biotechnology , mapk/erk pathway , insulin receptor , chemistry , signal transduction , kinase , protein kinase b , biochemistry , insulin , biology , endocrinology , insulin resistance
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. KEDQ YMKM TV, 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, C 1056 , C 1138 , or C 1234 , were examined for changes in fluorescence emission spectra in the presence of peptides. KYCCSRK and KEDQ YMKM TV 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.—Gibbs, P. E. M., Lerner‐Marmarosh, N., Poulin, A., Farah, E., Maines, M. D. Human biliverdin reductase‐based peptides activate and inhibit glucose uptake through direct interaction with the kinase domain of insulin receptor. FASEB J . 28, 2478–2491 (2014). www.fasebj.org