S6 Phosphorylation and the p70^s6k/p85^s6k

Abstract

Activation of cell growth leads to the multiple phosphorylation of 40S ribosomal protein S6. The kinase responsible for controling this event is termed p70s6k/p85s6k. Both isoforms of the kinase are derived from a common gene activated by a complex set of phosphorylation events; each resides in a unique cellular compartment: the p70s6k in the cytoplasm and the p85s6k in the nucleus. Although p70s6k/p85s6k represent the first mitogen-activated serine/threonine kinase described, the signaling pathway leading to activation of both isoforms remains obscure. Recent studies have shown that this pathway is distinct from that of p21ras and the p42mapk/p44mapk, and that bifurcation of these pathways takes place at the level of the receptor. Experiments with point mutants of the PDGF receptor and inhibitors of phosphatidyl-inositol-3-OH kinase have implicated the latter molecule in this signaling event, but more recent findings suggest an alternative route may be employed. The p70s6k signaling pathway can also be ablated by the immunosuppressant rapamycin, which blocks p70s6k activation and S6 phosphorylation without affecting the other kinases whose activation is triggered by mitogen treatment. In parallel, rapamycin suppresses the translation of a family of mRNAs that contain a polypyrimidine tract at their 5' transcriptional start site. The implication is that this event is mediated by the phosphorylated form of S6 that may either (1) directly interact with the polypyrimidine tract or (2) alter the affinity of the 40S ribosome mRNA binding site for polypyrimidine tract mRNAs, or (3) recognize proteins that directly bind to the polypyrimidine tract.

Unique, Highly Proliferative Growth Phenotype Expressed by Embryonic and Neointimal Smooth Muscle Cells Is Driven by Constitutive Akt, mTOR, and p70S6K Signaling and Is Actively Repressed by PTEN

“…S6RP has a known role in translation initiation and cell cycle progression and is a downstream effector of PI3K/Akt/ p70S6K signaling pathways. 5,6 We therefore hypothesized increased activity of this signaling pathway in embryonic and postinjury vessels may be associated with high growth rates. Using Western blot analysis on arterial tissues, we found increased levels of Akt and p70S6K phosphorylation in embryonic and postinjury vessels compared with adult aortic and sham-injured carotid artery vessels ( Figure 1B).…”

Dissociation of cAMP-stimulated Mitogenesis from Activation of the Mitogen-activated Protein Kinase Cascade in Swiss 3T3 Cells

“…Indeed, we could not demonstrate any activation of this enzyme by cAMP providing further corroborative evidence that the MAP kinase pathway was not activated (data not shown). A distinct S6 kinase family, p70/85kDa s6k , has been shown to be activated by a number of growth factors (42). Selective inhibition of the phosphorylation and activation of this kinase by the immunosuppressant rapamycin has suggested that p70 s6k plays a role in serum-stimulated DNA synthesis in Swiss 3T3 cells (33).…”

The Ras/Rac1/Cdc42/SEK/JNK/c-Jun Cascade Is a Key Pathway by Which Agonists Stimulate DNA Synthesis in Primary Cultures of Rat Hepatocytes

“…Hepatocytes were lysed and subjected to immunoprecipitation followed by immune complex kinase assays for JNK1. Hepatocytes were infected with either control virus or recombinant adenoviruses to express dominant-negative PI 3 kinase p110␣ and dominant-negative PI 3 kinase p110␥, and were treated 24 h later with either 50 mM glucose or 1 ng/ l HGF (Chung et al, 1992;Ferrari and Thomas, 1994;Franke et al, 1995;Vanhaesebroeck et al, 1997). Glucose and HGF treatments of control-infected hepatocytes activated p70 S6 kinase and inhibited GSK3 activities, modulations that were both blocked by coexpression of dominant-negative PI 3 kinase p110␣ and dominant-negative PI 3 kinase p110␥ (Figure 4).…”