Phosphorylation of kinase activation loop is an important and necessary stepfor achieving the activated Ire1 RNasesplicing state in which splicing of Xbp1 is enhanced, leading to subsequent activation of UPR signal.This study will help to clarify our understanding of Ire1-phosphoregulated RNase splicing and provide valuable insightsfor cancer therapeutic targeting of Ire1. This evidence concerns the gene ERN1 and cancer.