ERK Phosphorylates p66shcA on Ser36 and Subsequently Regulates p27^kip1Expression via the Akt-FOXO3a Pathway: Implication of p27^kip1in Cell Response to Oxidative Stress

Abstract

Mice deficient for p66shcA represent an animal model to link oxidative stress and aging. p66shcA is implicated in oxidative stress response and mitogenic signaling. Phosphorylation of p66shcA on Ser36 is critical for its function in oxidative stress response. Here we report the identification of ERK as the kinase phosphorylating p66shcA on Ser36. Activation of ERKs was necessary and sufficient for Ser36 phosphorylation. p66shcA interacted with ERK and was demonstrated to be a substrate for ERK, with Ser36 being the major phosphorylation site. Furthermore, in response to H2O2, inhibition of ERK activation repressed p66shcA-dependent phosphorylation of FOXO3a and the down-regulation of its target gene p27kip1. Down-regulation of p27 might promote cell survival, as p27 played a proapoptotic role in oxidative stress response. As a feedback regulation, Ser36 phosphorylated p66shcA attenuated H2O2-induced ERK activation, whereas p52/46shcA facilitated ERK activation, which required tyrosine phosphorylation of CH1 domain. p66shcA formed a complex with p52/46ShcA, which may provide a platform for efficient signal propagation. Taken together, the data suggest there exists an interplay between ERK and ShcA proteins, which modulates the expression of p27 and cell response to oxidative stress.

Icariin delays homocysteine-induced endothelial cellular senescence involving activation of the PI3K/AKT-eNOS signaling pathway

“…Pretreatment by ICA induced significantly activation of ERK and AKT. There are reports that indicated ERK was involved in H 2 O 2 -induced cell response (Hu et al, 2005). In the present study, the concentration of homocysteine was up to 400 μM, thus we deduced that the increase of Figure 6.…”

Post-translational modifications of FOXO family proteins

“…Previous studies have reported the association between ERK, p66 shc adaptor protein 1 (p66shcA) and FOXO3. The phosphorylation of p66shcA Ser36 is required for phosphorylation of FOXO3a, which can be induced by ERK1/2 (48). In cardiac fibroblasts, activation of ERK1/2 can directly phosphorylate FOXO3a and regulate its activity, and ERK1/2 can also phosphorylate Skp2 in the same manner.…”

“…In cardiac fibroblasts, activation of ERK1/2 can directly phosphorylate FOXO3a and regulate its activity, and ERK1/2 can also phosphorylate Skp2 in the same manner. Notable, a report previously demonstrated that Skp2 can inhibit the activity of FOXO3a and promote its degradation (48,49). SGK is another link between MAPK and FOXO proteins.…”

Inhibition of p66ShcA Longevity Gene Rescues Podocytes from HIV-1-induced Oxidative Stress and Apoptosis

“…p66ShcA has emerged as a genetic determinant of longevity in mammals (10) that controls mitochondrial metabolism and cellular responses to oxidative stress, aging, and apoptosis. The potent stress response regulator Foxo3A is a downstream target of p66ShcA redox signals that phosphorylate key regulatory sites, inhibiting transcription of Foxo3A stress-related gene products (11,12). Because phosphorylation at a critical Ser-36 residue activates p66ShcA redox activity (13), mutation at this site should inhibit transmission of reactive oxygen species (ROS)-dependent signals…”