Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis.

By Igor Ruvinsky, N. Sharon, Tal Lerer, H. Cohen, M. Stolovich-Rain, T. Nir, Yuval Dor, P. Zisman, O. Meyuhas. Genes & Development, 2005

652 citations recorded by the source corpus.

The regulated phosphorylation of ribosomal protein (rp) S6 has attracted much attention since its discovery in 1974, yet its physiological role has remained obscure. To directly address this issue, we have established viable and fertile knock-in mice, whose rpS6 contains alanine substitutions at all five phosphorylatable serine residues (rpS6(P-/-)). Here we show that contrary to the widely accepted model, this mutation does not affect the translational control of TOP mRNAs. rpS6(P-/-) mouse embryo fibroblasts (MEFs) display an increased rate of protein synthesis and accelerated cell division, and they are significantly smaller than rpS6(P+/+) MEFs. This small size reflects a growth defect, rather than a by-product of their faster cell division. Moreover, the size of rpS6(P-/-) MEFs, unlike wild-type MEFs, is not further decreased upon rapamycin treatment, implying that the rpS6 is a critical downstream effector of mTOR in regulation of cell size. The small cell phenotype is not confined to embryonal cells, as it also selectively characterizes pancreatic beta-cells in adult rpS6(P-/-) mice. These mice suffer from diminished levels of pancreatic insulin, hypoinsulinemia, and impaired glucose tolerance.

Subfields: Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/8ca82e663d2d2e650e56ffce8c596099741a4201

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Citations in the corpus

THE MECHANISM OF EUKARYOTIC TRANSLATION INITIATION AND PRINCIPLES OF ITS REGULATION (2010, background): “On the contrary, in the case of rpS6 phosphorylation, although the correlation with increased translation seems particularly striking, cells derived from the embryos of rpS6 kinase 1 and rpS6 kinase 2 double knockout mice, or knock-in of an rpS6 gene with all five phosphorylation sites mutated to Al”
Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. (2008, background): “Phosphorylated S6K1 in turn phosphorylates ribosomal protein S6, an essential regulator of protein translation and cell growth (Ruvinsky et al. 2005).”
Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress (2010, background): “A better understanding of how stress responses impinge upon mTORC1 as a function of time may inform the timing and dosage of therapeutics aimed at manipulating mTORC1 activity in various disease states.”
TOR signaling in growth and metabolism. (2006, background): “However, this model has now lost favor due to the recent findings that translation of 5′TOP mRNAs does not depend on S6K (S6K1 and S6K2) activity nor on S6 phosphorylation (Pende et al., 2004; Ruvinsky et al., 2005).”
Molecular mechanisms of mTOR-mediated translational control (2009, background): “Similarly, ribosomal protein S6 (RPS6), which is often used as a biomarker for S6K activity, does not seem to be the crucial target of S6Ks in regulating cell growt”