PHOSPHORYLATION OF RIBOSOMAL PROTEIN S6 IS A DETERMINANT OF THE SIZE AND FUNCTION OF BETA CELLS AND MYOBLASTS

A. DREAZEN; M. KATZ; I. RUVINSKY; A. SAADA-REISCH; N.C. FRIEDMAN; G. ZIMMERMAN; O. MEYUHAS

Eilat, Israel

Congreso; ILANIT; 2008

Comisión Israelí de biología molecular y desarrollo

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 knockin mice, rpS6P-/-, whose rpS6 contains alanine substitutions at all five phosphorylatable serine residues. Phenotypic characterization of these mice, and embryo fibroblasts derived from them, has established the role of these residues in cell size regulation, in â-cell function and glucose disposal. We have examined the role of rpS6 phosphorylation in transduction of signals emanating from the Akt1 (PKBalpha) kinase, by establishing double-mutant mice that are rpS6 phosphorylation deficient and Akt1 overexpressors. These mice clearly show that Akt1 overexpression completely overrides the deleterious effect of rpS6 phosphorylation deficiency on both the pancreatic beta-cell size and glucose homeostasis. These results imply that the beta-cell hypertrophy and glucose hyper-tolerance in Akt1 transgenic mouse are exerted in an rpS6 phosphorylation-independent fashion. The deleterious effect of rpS6 phosphorylation deficiency is not confined to beta-cells, as the knockin mice exhibit compromised physical strength. This physical inferiority does not reflect impaired glucose uptake, decreased glycogen storage or diminished activity of complexes of the mitochondrial oxidative phosphorylation system. Instead, it seems to primarily reflect smaller size of the myoblasts that constitute the muscle fiber and consequently a decreased mass of the entire muscle.