14 Ribosomal Protein S6 Phosphorylation and Signal Transduction

Growth factors, acting through single transmembrane tyrosine kinase receptors or G-protein-coupled serpentine receptors, induce cells in the animal and in culture to exit the G 0 state of the cell cycle, progress through G 1 , synthesize DNA, and divide (Bourne et al. 1990; Cantley et al. 1991). This process is accomplished through the coordinate activation of a number of metabolic events (Pardee 1989). It has become evident during the last 5–10 years that the major intracellular mediator of these events is protein phosphorylation/dephosphorylation (Krebs 1994). The realization of the importance of this regulatory mechanism to cell growth has focused a great deal of attention on the identification of substrates and the signaling pathways that control cell cycle progression (Egan and Weinberg 1993; Downward 1994). One of the early obligatory metabolic events involved in the induction of cell growth is the activation of protein synthesis (Pardee 1989), a process that proceeds through a complex set of steps involving a large number of translational components (see Morley and Thomas 1991), including initiation factors, tRNA Met , mRNA, and the 40S and 60S ribosomal subunits. The rate-limiting event in increased protein synthesis is thought to be the recognition and binding of mRNA by the 43S ribosomal preinitiation complex, a step that also requires a family of initiation factors termed 4A, 4B, and 4F (Sonenberg 1994; see Mathews et al.; Sonenberg; both this volume). In turn, this process is thought to be regulated by the concerted phosphorylation and dephosphorylation of key translational components (see Morley and Thomas...