Insulin signaling and the control of PHAS-I phosphorylation.

Abstract

The rate of mRNA translation is determined by many factors including a family of proteins that control the availability of the mRNA cap-binding protein, eIF4E. The prototypic member of this family was originally described as a protein that became phosphorylated when rat adipocytes were exposed to insulin (Belsham and Denton 1980), a finding that presaged the important role of phosphorylation in controlling the protein’s function. The phosphorylated protein had the unusual properties of remaining in solution when boiled or exposed to acid (Belsham and Denton 1980), and it was named PHAS-I (phosphorylated heat- and acid-stable) after its cDNA was found to lack homology with any others encoding known proteins (Hu et al. 1994). Subsequently, PHAS-I was found to be an eIF4E-binding protein, and named 4E-BP1 (Pause et al. 1994). We have retained the earlier nomenclature and will refer to the family as PHAS proteins. Mammals and many lower organisms including slime mold, insects, fish, and birds express one or more members of this family (Fig. 1A). The proteins have not been found in plants or yeast, although the latter contain an eIF4E-binding protein that possibly serves a homologous function but which has no amino acid sequence identity with the PHAS proteins, except in the eIF4E binding domain (Zanchin and McCarthy 1995). Thus, the distribution of PHAS proteins in nature appears less widespread than that of eIF4E, which is probably expressed in all eukaryotic organisms. Nevertheless, in mammals and many other species, PHAS proteins are important mediators of the actions of insulin, growth factors and nutrients on protein synthesis.