eIF2 activity is regulated by a mechanism involving both guanine nucleotide exchange and phosphorylation. Phosphorylation takes place at the α-subunit, which is a target for a number of serine kinases that phosphorylate serine 51. Those kinases act as a result of stress such as amino acid deprivation (GCN2), ER stress (PERK), the presence of dsRNA (PKR) heme deficiency (HRI), or interferon. Once phosphorylated, eIF2 shows increased affinity for eIF2B, its GEF. However, eIF2B is able to exchange GDP for GTP only if eIF2 is in its unphosphorylated state. Phosphorylated eIF2, however, due to its stronger binding, acts as an inhibitor of its own GEF (eIF2B). Since the cellular concentration of eIF2B is much lower than that of eIF2, even a small amount of phosphorylated eIF2 can completely abolish eIF2B activity by sequestration. Without the GEF, eIF2 can no longer be returned to its active (GTP-bound) state. As a consequence, translation comes to a halt since initiation is no longer possible without any available ternary complex. Furthermore, low concentration of ternary complex allows the expression of GCN4 (starved condition), which, in turn, results in increased activation of amino acid synthesis genes