Modulation of Obesity and Insulin Resistance by the Redox Enzyme and Adaptor Protein p66Shc

Abstract

Initially reported as a longevity-related protein, the 66 kDa isoform of the mammalian Shc1 locus has been implicated in several metabolic pathways, being able to act both as an adaptor protein and as a redox enzyme capable of generating reactive oxygen species (ROS) when it localizes to the mitochondrion. Ablation of p66^Shc has been shown to be protective against obesity and the insurgence of insulin resistance, but not all the studies available in the literature agree on these points. This review will focus in particular on the role of p66^Shc in the modulation of glucose homeostasis, obesity, body temperature, and respiration/energy expenditure. In view of the obesity and diabetes epidemic, p66^Shc may represent a promising therapeutic target with enormous implications for human health.

Keywords: adipose tissue; aging; diabetes; glucose tolerance; metabolic syndrome; muscle; oxidative stress.

Figure 1

Role of p66^Shc in signal transduction. (A) p52^Shc and p46^Shc are activated by phosphorylation in tyrosine residues within their CH1 domain, when bound to RTKs and possibly other receptors. Subsequently, the recruitment of the Grb2/Sos1 complex allows for the activation of Ras and the MAPK pathway. p66^Shc can compete with the other two isoforms for the binding of Grb2, interfering with Ras activation. (B) After being activated by RTKs, and the concomitant phosphorylation in Ser³⁶ by kinases such as PKCβ or JNK, p66^Shc is subjected to cis-trans isomerization by Pin1. It then translocates to the inter-membrane space of the mitochondrion, after being dephosphorylated by PP2A. Without stimulation, p66^Shc is bound to other proteins, like HSP70, and therefore is inactive. After stimulation with UV-light or H₂O₂, p66^Shc can bind to cytochrome c and contribute to the formation of ROS. See the main text for further details.