Novel Insights into the PKCβ-dependent Regulation of the Oxidoreductase P66Shc

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2016 Sep 15

PMID 27624939

Citations 14

Authors

Martina Haller

Sana Khalid

Leopold Kremser

Friedrich Fresser

Tobias Furlan

Martin Hermann

Julia Guenther

Astrid Drasche

Michael Leitges

Marco Giorgio

Gottfried Baier

Herbert Lindner

Jakob Troppmair

Affiliations

Soon will be listed here.

Abstract

Dysfunctional mitochondria contribute to the development of many diseases and pathological conditions through the excessive production of reactive oxygen species (ROS), and, where studied, ablation of p66Shc (p66) was beneficial. p66 translocates to the mitochondria and oxidizes cytochrome c to yield HO, which in turn initiates cell death. PKCβ-mediated phosphorylation of serine 36 in p66 has been implicated as a key regulatory step preceding mitochondrial translocation, ROS production, and cell death, and PKCβ thus may provide a target for therapeutic intervention. We performed a reassessment of PKCβ regulation of the oxidoreductase activity of p66. Although our experiments did not substantiate Ser phosphorylation by PKCβ, they instead provided evidence for Ser and Ser as PKCβ phosphorylation sites regulating the pro-oxidant and pro-apoptotic function of p66. Mutation of another predicted PKCβ phosphorylation site also located in the phosphotyrosine binding domain, threonine 206, had no phenotype. Intriguingly, p66 with Thr and Ser mutated to glutamic acid showed a gain-of-function phenotype with significantly increased ROS production and cell death induction. Taken together, these data argue for a complex mechanism of PKCβ-dependent regulation of p66 activation involving Ser and a motif surrounding Ser.

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