The human biliverdin reductase-based peptide fragments and biliverdin regulate protein kinase Cδ activity: the peptides are inhibitors or substrate for the protein kinase C.

The Journal of Biological Chemistry
Tihomir MiralemMahin D Maines

Abstract

PKCδ, a Ser/Thr kinase, promotes cell growth, tumorigenesis, and apoptosis. Human biliverdin reductase (hBVR), a Ser/Thr/Tyr kinase, inhibits apoptosis by reducing biliverdin-IX to antioxidant bilirubin. The enzymes are activated by similar stimuli. Reportedly, hBVR is a kinase-independent activator of PKCδ and is transactivated by the PKC (Gibbs, P. E., Miralem, T., Lerner-Marmarosh, N., Tudor, C., and Maines, M. D. (2012) J. Biol. Chem. 287, 1066-1079). Presently, we examined interactions between the two proteins in the context of regulation of their activities and defining targets of hBVR phosphorylation by PKCδ. LC-MS/MS analysis of PKCδ-activated intact hBVR identified phosphorylated serine positions 21, 33, 230, and 237, corresponding to the hBVR Src homology-2 domain motif (Ser(230) and Ser(237)), flanking the ATP-binding motif (Ser(21)) and in PHPS sequence (Ser(33)) as targets of PKCδ. Ser(21) and Ser(230) were also phosphorylated in hBVR-based peptides. The Ser(230)-containing peptide was a high affinity substrate for PKCδ in vitro and in cells; the relative affinity was PKCδ > PKCβII > PKCζ. Two overlapping peptides spanning this substrate, KRNRYLSF and SFHFKSGSL, were effective inhibitors of PKCδ kinase activity and...Continue Reading

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Citations

Jun 20, 2015·Frontiers in Pharmacology·Peter E M GibbsMahin D Maines
Aug 5, 2017·International Journal of Molecular Sciences·Olena S OliinykVladislav V Verkhusha
Mar 2, 2018·American Journal of Physiology. Gastrointestinal and Liver Physiology·Lauren WeaverTerry D Hinds
May 12, 2016·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Tihomir MiralemMahin D Maines
Feb 23, 2020·Frontiers in Immunology·Giacomo CanesinBarbara Wegiel
Jun 20, 2019·Biochemistry. Biokhimii︠a︡·M M KarasevV V Verkhusha
Aug 4, 2018·Molecular Neurobiology·Eugenio BaroneMarzia Perluigi
Jul 6, 2021·Free Radical Biology & Medicine·Cesare Mancuso

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