PERK (encoded in humans by the gene EIF2AK3) responds mainly to endoplasmic reticulum stress and has two modes of activation. This kinase has a unique luminal domain that plays a role in activation. The classical model of activation states that the luminal domain is normally bound to 78-kDa glucose-regulated protein (GRP78). Once there is a buildup of unfolded proteins, GRP78 dissociates from the luminal domain. This causes PERK to dimerize, leading to autophosphorylation and activation. The activated PERK kinase will then phosphorylate eIF2α, causing a cascade of events. Thus, the activation of this kinase is dependent on the aggregation of unfolded proteins in the endoplasmic reticulum. PERK has also been observed to activate in response to activity of the proto-oncogene MYC. This activation causes ATF4 expression, resulting in tumorigenesis and cellular transformation.