S6K1 Regulates GSK3 under Conditions of mTOR-Dependent Feedback Inhibition of Akt

Abstract

Feedback inhibition of the PI3K-Akt pathway by the mammalian target of rapamycin complex 1 (mTORC1) has emerged as an important signaling event in tumor syndromes, cancer, and insulin resistance. Cells lacking the tuberous sclerosis complex (TSC) gene products are a model for this feedback regulation. We find that, despite Akt attenuation, the Akt substrate GSK3 is constitutively phosphorylated in cells and tumors lacking TSC1 or TSC2. In these settings, GSK3 phosphorylation is sensitive to mTORC1 inhibition by rapamycin or amino acid withdrawal, and GSK3 becomes a direct target of S6K1. This aberrant phosphorylation leads to decreased GSK3 activity and phosphorylation of downstream substrates and contributes to the growth-factor-independent proliferation of TSC-deficient cells. We find that GSK3 can also be regulated downstream of mTORC1 in a HepG2 model of cellular insulin resistance. Therefore, we define conditions in which S6K1, rather than Akt, is the predominant GSK3 regulatory kinase.

Blebbishields, the emergency program for cancer stem cells: sphere formation and tumorigenesis after apoptosis

“…N, nucleus; C, cytoplasm; aNu, active nucleolus; cNu, cytoplasmic nucleolus; NM, nuclear membrane (also see Supplementary Figure S1) (e) Requirement of cisplatin, lithium chloride, and NEAA þ Vitamin deprivation to increase the number of blebbishields but to reduce necrosis Ser-9 in TSC-2 null cells without Akt activation. 15 Interestingly, p70S6K activation correlated with increased GSK-3b Ser-9 phosphorylation (Figure 1b).…”

Ex Vivo Rapamycin Generates Apoptosis-Resistant Donor Th2 Cells That Persist In Vivo and Prevent Hemopoietic Stem Cell Graft Rejection

“…Finally, as a fourth possibility, we hypothesized that rapamycin resistance in Th2.R cells might be associated with inhibition of GSK3␤), which induces T cell apoptosis or cell cycle arrest (46). Of note, it has recently been shown that the mTOR and GSK3␤ pathways are interrelated (47). We found that the inactive, phosphorylated form of GSK3␤ was overexpressed in Th2.R cells relative to control Th2 cells (six of six cases).…”

GSK‐3β‐dependent destabilization of cyclin D1 mediates replicational stress‐induced arrest of cell cycle

“…This was accompanied by transient activation of GSK-3b through dephosphorylation of Serine-9. Although, GSK-3b activity returned to normal in the presence of continued Akt inactivation involving other kinases such as S6K1 [29]. Thus, GSK-3b appears to be an arbiter of cell fate towards proliferation, arrest or apoptosis.…”