14 Signaling to Translation Initiation

Abstract

Following transcription and several nuclear processing events (including splicing, a quality control step, the “pioneer” round of translation, and nucleocytoplasmic transport), eukaryotic mRNAs are competent for translation. However, ribosomes alone lack the ability to identify and position themselves at an initiation codon. Instead, the protein synthetic machinery must be recruited to the mRNA 5′ end via the concerted action of the eukaryotic translation initiation factors (eIFs). This complex recruitment process, also referred to as the initiation phase of translation, culminates in the positioning of a charged ribosome (i.e., an 80S ribosome loaded with an initiator methionyl-tRNA in its P site) at an initiation codon (for a more complete description of this process, see Chapter 4). The initiation process is rate-limiting for translation in many cases and is subject to exquisite regulation.

Early studies indicated that translation rates are primarily regulated at the initiation phase and are tightly controlled in response to extracellular stimuli and stresses or changes in local environmental conditions: for example, hormone/growth factor signals, amino acid or nutrient availability, and environmental stresses such as heat or osmotic shock (see Chapter 13). Moreover, precise (often localized) regulation of the translation of specific mRNAs or mRNA classes is critical for the proper progression of a variety of physiological and developmental processes (e.g., to establish protein gradients in developing embryos or learning and memory formation). Dysregulation of translational control may also be an important component of cellular transformation (Chapter 15).

Many of the translation initiation factors were demonstrated to be phosphoproteins...