Cellular function of p70^S6K: A role in regulating cell motility

Abstract

The 70 kDa ribosomal S6 kinase (p70 S6K ) is activated through the phosphoinositide (PI) 3-kinase-regulated pathway (Fig. 1). This pathway is responsible for the generation of inositol lipids, which are key mediators of intracellular signalling. Multiple isoforms of PI 3-kinase have been identified and classed according to substrate specificity and structure. 1 Class I PI 3-kinase is involved in receptor-induced hormonal responses and the mechanism of activation of this enzyme differs depending on the particular extracellular stimuli. For tyrosine kinase-coupled receptor systems, p110 catalytic subunits α, β and δ are stimulated through interaction with the p85 adaptor subunit, which binds selectively through its SH2 domain to phosphorylated tyrosines on the activated receptor. 2 For G-protein-coupled receptor systems, the signalling for PI 3-kinase activation is less clear and several mechanisms have been suggested. A number of reports have identified a p110γ catalytic subunit, which is activated through binding either directly to the βγ subunits of activated trimeric G-proteins 3 or through interaction with a p101 adaptor protein. 4,5 Other studies have suggested alternative mechanisms involving G-protein-mediated activation of receptor tyrosine kinase activity 6 or through the p110β isoform, which can also be activated directly by G-protein βγ subunits. 7 For both receptor systems, PI 3-kinase catalyses the phosphorylation of phosphoinositides at the 3′-OH position. For hormone-induced responses in vivo, phosphatidylinositol 4,5-bisphosphate (PI-4,5P 2 ) is the primary substrate for PI 3-kinase, leading to the production of phosphatidylinositol 3,4,5-trisphosphate (PI-3,4,5P 3 ). Phosphatidylinositol 3,4,5P 3 is also rapidly dephosphorylated by 5′-phosphatases, giving rise to the production of phosphatidylinositol 3,4-bisphosphate (PI-3,4P 2 ). 8 Although the mechanism regulating the relative levels of these two phospholipids is complex, both are thought to act as second messengers in cellular responses such as mitosis, apoptosis, membrane trafficking, motility, differentiation and oncogenic transformation by targeting certain pleckstrin homology (PH) domain-containing proteins to the plasma membrane. 9 Two isoforms of p70 S6K have been identified: a 70 kDa cytoplasmic form and a 85 kDa nuclear form. The sequence of the longer form includes a 23 amino acid nuclear localization sequence at the amino terminus. The molecular sequences of these two isoforms are otherwise the same and can be jointly referred to as p70 S6K or S6K1. Recently, a second functional homologue, S6K2, has been identified. This second S6 kinase shows similar sensitivity to rapamycin and PI 3-kinase inhibitors and is upregulated in p70 S6K1 -deficient mice. 10,11 The identification of S6K2 has raised the possibility that some functional responses of S6K1 may be caused by activation of S6K2 or even other unidentified S6 kinases.Activation of p70 S6K occurs through a complex series of phosphorylation events on eight or more serine or threoni...

Granulocyte-Macrophage Colony-Stimulating Factor Is a Chemoattractant Cytokine for Human Neutrophils: Involvement of the Ribosomal p70 S6 Kinase Signaling Pathway

“…11) suggests that this downstream signaling link may be of particular importance. These findings add to previous observations that rapamycin prevents neutrophil Ca 2ϩ -associated stress fiber formation in neutrophils (50) and that p70S6K colocalizes with actin stress fibers near the forward edge of migrating 3T3 fibroblasts (51). We have recently shown that rapamycin inhibits GM-CSF-induced actin polymerization (52) and that it has a direct inhibitory effect on p70S6K T 421 /S 424 and T 389 phosphorylation, which can be rescued by the immunophilin FK506 (33).…”

ILK mediates actin filament rearrangements and cell migration and invasion through PI3K/Akt/Rac1 signaling

“…Our results are also consistent with the recent observation that p70S6K1 is activated in insulin, PDGF, and EGF signaling (Burgering and Coffer, 1995). p70S6K1 is localized at the areas of actin stress fibers and actin arc, an actin structure at the leading edge of the cells during cell movement (Berven and Crouch, 2000). In previous studies, both our group and Blenis' group found that overexpression of a constitutive active form of p70S6K1 is sufficient to induce actin filament rearrangements in different cells (Chou and Blenis, 1996;Qian et al, 2004).…”

Phosphatidic Acid Is a Leukocyte Chemoattractant That Acts through S6 Kinase Signaling

“…S6K colocalizes with those stress fibers in the lamellipodia of moving leukocytes (42), and its phosphorylation induces migration of vascular smooth cells (43,44) and chick embryo fibroblasts (45). S6K mediates leukocyte chemotaxis induced by the human growth factor GM-CSF, which is inhibited by rapamycin at subnanomolar concentrations.…”