p70S6K Signaling


Pathway Description

The p70S6K protein is a Serine/Threonine kinase that phosphorylates the ribosomal S6 subunit, a component of the 40S subunit of eukaryotic ribosomes. It plays a role in protein synthesis and in cell growth control during G1 phase via enhanced translation of certain mRNA species. This enzyme has a complex regulation: phosphorylation by PDK1 at the activation loop is required for activation. Activity is also modulated by phosphorylation by ERK1 and ERK2 and dephosphorylation by phosphatases. The mTOR Serine/Threonine kinase is also required for full activation of p70S6K.p70S6K is activated through a complex network of signaling molecules. The enzymatic activity of p70S6K is stimulated by GM-CSF in hematopoietic cell and neutrophils. The generation of 3-phosphoinositide lipid products by PI3K, which is activated in response to ligands such as angiotensin II, EGF, insulin and IGF1, is required for the phosphorylation of p70S6K by PDK1, AKT and mTOR. PI3K, which is important for activation of p70S6K, can be activated by several proteins. In thrombin signaling, binding of thrombin to its receptor PAR-1 leads to the activation of PI3K via Gαi. In B cells, identification of a novel B cell adaptor termed BCAP, has been reported to activate PI3K.

Mechanical stimuli activate p70S6K via mTOR signaling through a PLD-dependent increase in PA. The downstream mediator of AKT/p70S6K signaling regulates mRNA translation and cell cycle progression. Both AKT and p70S6K are capable of phosphorylating and inactivating BAD, thus regulating cell death.

mTOR controls multiple cellular functions in response to amino acids and growth factors. For effective mTOR-catalyzed p70S6K phosphorylation, the disruption of the ternary complex of mTOR-RAPTOR-p70S6K is necessary. AKT and p70S6K are actively involved in mediating cell adhesion. p70S6K regulates cell growth by inducing protein synthesis in response to cytokines. IL-4 activates p70S6K via PI3K and PKC-δ. The IL-4 receptors (IL-4Ralpha; and IL-4Rγ) induce JAK1 to activate IRS which in turn modulates PI3K.

p70S6K is also an important regulator of cell proliferation. Its activation by growth factors requires an ERK-dependent signal. Constitutive p70S6K activation occurs in some human malignancies and may contribute to dysregulated cell growth. FRAP-p70S6K signaling appears to be necessary for G1-S phase progression and proliferation in pancreatic cancer cells. Rapamycin, a specific inhibitor of p70S6K, inhibits functional chemotaxis which is induced by p70S6K through MAPK signaling.

p70S6K phosphorylates the 40S ribosomal protein S6, modulating the translation of an mRNA subset that encodes ribosomal proteins and translation elongation factors. p70S6K is activated in response to mitogenic stimuli and is required for progression through the G1 phase of the cell cycle and for cell growth. Besides S6, other important targets of p70S6K include the microtubule associated protein Tau. A p70S6K-modulated up-regulation of Tau translation might contribute to PHF-tau accumulation in neurons with neurofibrillary changes. p70S6K also phosphorylates Ser366 of eEF2K, causing inactivation which also leads to protein synthesis. Thus p70S6K is known for its role in modulating cell cycle progression, cell size and cell survival. In response to mitogen stimulation, p70S6K activation up-regulates ribosomal biosynthesis and enhances the translational capacity of the cell.