p70S6K Signaling
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p70S6K Signaling
p70S6K is a protein Ser-Thr 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 in vivo to enhance translation of certain mRNA species. This enzyme has complex regulation: Phosphorylation by PDK-1 (Phosphoinositide Dependent Kinase-1) at the activation loop is required for activation. Activity is also modulated due to phosphorylation by ERK1 (Extracellular Signal-Regulated Kinase-1) and ERK2 (Extracellular Signal-Regulated Kinase-2) protein Ser-Thr kinases and by dephosphorylation by Phosphatases. The mTOR (Mammalian Target of Rapamycin) protein Ser-Thr kinase is also required to full activation of p70S6K. p70S6K is itself a dual pathway kinase, signaling cell survival as well as growth through differential substrates, which include mitochondrial BAD (Bcl2-Antagonist of Cell Death) and the ribosomal subunit S6, respectively.

In the living cell, ribosomal p70S6K is activated through a complex network of signaling molecules. The enzymatic activity of p70S6K is stimulated by GM-CSF (Granulocyte Macrophage Colony-Stimulating Factor) in hematopoietic cell and neutrophils. GM-CSF modifies the Vmax of the enzyme and induced a time and dose dependent phosphorylation on p70S6K residues Thr389 and Thr421/Ser424. Phosphorylation of either Thr389 or Thr421/Ser424 on p70S6K is necessary but not sufficient to achieve full activation. The generation of 3-phosphoinositide lipid products by PI3K (Phosphatidylinositde-3 Kinase) is required for the phosphorylation of two activating sites in p70S6K: Thr229 and Thr389. Thr229 is phosphorylated by PDK-1, mTOR/FRAP, Akt/PKB and PKC-Zeta. GM-CSF activates PI3K/Akt via a series of proteins and promotes cell survival via p70S6K (Ref.1).

Insulin modulates the p70S6K through its downstream target Akt. Cardioprotection via insulin is independent of glucose and is mediated, in part, via Akt, p70S6K and BAD cell survival effects. In Insulin-mediated myocardial protection, PI3K appears to be part of a cascade and can activate Akt, which in turn activate mTOR and p70S6K. The downstream mediator of Akt -p70S6K that is important in regulating a variety of cellular functions including mRNA translation and cell cycle progression. An additional cell survival target of Akt is the cytosolic proapoptotic peptide BAD can be sequestering in the cytosol if maintained in a phosphorylated state on either of the two serine residues (Ser112 and 136) embedded in the 14-3-3 consensus binding sites, thus affecting the cell survival. Both Akt and p70S6K are capable of phosphorylating Ser136 and thereby inactivating BAD, thus regulating the cell death (Ref.2).

The mTOR controls multiple cellular functions in response to amino acids and growth factors in part by regulating the phosphorylation of p70S6K. RAPTOR (Regulatory Associated Protein of mTOR) binds to the p70S6K through its TOS (conserved TOR signaling) motifs. The recognition of p70S6K by RAPTOR requires an intact p70S6K TOS motif. For effective mTOR-catalyzed p70S6K phosphorylation, the disruption of the ternary complex of mTOR-RAPTOR-p70S6K is necessary. In addition, mTOR can phosphorylate prokaryotic recombinant fragments of p70S6K that lack entirely the N-terminal region containing the TOS motif on a variety of sites, including Thr-412 (Ref.3).

Akt/PKB and p70S6K are actively involved in mediating cell adhesion and spreading on Galectin-8. Their positive role is particularly evident in cells overexpressing PKB or p70S6K, whose adhesion and spreading is inhibited in the presence of PI3K inhibitors. The role of PKB or p70S6K as positive regulators of cell adhesion is in accordance with the fact that ligation of growth factor receptors, which stimulates the activity of PKB or p70S6K, potentiates the adhesive process in a number of cell types. Protein substrates for PKB or p70S6K are phosphorylated to a higher extent in cells adherent to Galectin-8 and this enables them to replace other signaling molecules that promote cell adhesion (Ref.4).

A pocket in the kinase domain of PDK-1, termed the PIF-binding pocket, plays a key role in mediating the interaction and phosphorylation of p70S6K and SGK1 at their T-loop motif by PDK-1. The PIF-binding pocket represents a substrate recognition site on a protein kinase that is only required for the phosphorylation of a subset of its physiological substrates. These kinases are activated in a PI3K-dependent manner in response to Insulin/ Growth Factors signaling. Inhibition of p70S6K, and a concomitant decline in S6 phosphorylation leads to decrease in TOP mRNA (i.e. mRNAs containing a 5-terminal oligopyrimidine (TOP) motif) translation (Ref.5).

p70S6K regulates cell growth by inducing protein synthesis components, signaled through cytokines. IL-4 and IL-3 activate the p70S6K via PI3K and PKC-Delta respectively. The IL-R induces the JAK1 to activate the IRS, which in turn, then modulates PI3K. The p70S6K brings site specific phosphorylation of BAD, which inactivates the proapoptotic molecule (Ref.6).

p70S6K is an important regulator of cell proliferation. Its activation by growth factor requires sequential phosphorylation at Proline-directed residues in the putative autoinhibitory pseudosubstrate domain, as well as Threonine 389. Threonine 229, a site in the catalytic loop is phosphorylated by PDK-1. The p70S6K activation requires a PI3K-dependent signal(s). PI3K regulates uncharacteristic PKC isoform PKC-Zeta as an upstream regulator of p70S6K. Activation of PKC-Zeta by PI3K is mediated by either PDK-1 or PIP3. A kinase-inactive PKC-Zeta mutant antagonized activation of p70S6K by epidermal growth factor, PDK-1, and activated CDC42 and PI3K. Moreover, p70S6K can associate with both PDK-1 and PKC-Zeta in vivo in a growth factor-independent manner, while PDK-1 and PKC-Zeta can also associate with each other, suggesting the existence of a multimeric PI3K signaling complex (Ref.7).

p38 MAPK functions in BMP4 (Bone Morphogenetic Protein-4)-stimulated VEGF synthesis as a positive regulator at a point upstream from p70S6K in osteoblasts (Ref.8). Constitutive p70S6K activation occurs in some human malignancies and may contribute to dysregulated cell growth. FRAP-p70S6K signaling appears to be necessary for G(1)-to-S phase progression and proliferation in pancreatic cancer cells (Ref.9). Rapamycin, a specific inhibitor of p70S6K, inhibits the functional chemotaxis, which is induced by p70S6K through input from MAPK (Ref.10).

The 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 G(1) phase of the cell cycle and for cell growth. Activation of p70S6K is regulated by phosphorylation of seven different residues distributed throughout the protein, a subset of which depends on the activity of p85/p110 PI3K. In the full-length enzyme, however, these sites are also acutely sensitive to the action of FRAP (FKBP-12 Rapamycin-Associated Protein). The p85 regulatory subunit of PI3K also controls p70S6K activation by mediating formation of a ternary complex with p70S6K and FRAP. The p85 C-terminal SH2 domain is responsible for p85 coupling to p70S6K and FRAP, because deletion of the C-terminal SH2 domain inhibits complex formation and impairs p70S6K activation by PI3K (Ref.11). Insulin Receptors mediate PI3K and p70S6K activation during insulin stimulation (Ref.12).