UC San Diego

Eukaryotic Translation Initiation is governed by large initiation factor complexes, whose subunits are regulated in a largely discordant fashion. The Alliance for Cellular Signaling (AfCS) murine B cell single ligand screen with 33 ligands utilizing Agilent microarrays was analyzed for its effects on initiation factor gene expression. These ligands included those that stimulate receptor classes such as GPCR, kinase receptors, TNF superfamily receptors and immunoglobulin receptors. These receptors act in pathways such as NFkB, STAT6, JNK, ERK, PI(3)K, GPCR, cytokine signaling and interferon signaling. eIF2, which is inactivated upon phosphorylation of subunit 1 by alpha kinases 1-4, was seen to have discordant regulation of subunits and differing levels of kinase gene expression for different ligands, indicating a high degree of variability in global translation. eIF3, a large complex with at least 10 subunits, is seen to have discordant regulation of its subunits as well, even for a conserved 'core' complex, attesting to their dual functions in cellular machinery. eIF4, a complex consisting of 3 subunits with multiple subunit isoforms, was seen to express only eIF4G isoform 3 in murine B cells. eIF4A expression was limited to two isoforms, eIF4A and eIF4A3. Similar to eIF2s1, eIF4E can be phosphorylated by binding proteins, and these are seen to have differing levels of gene expression with various ligand stimulations, allowing for large variability in protein synthesis.