Proposed scheme depicting the relationship between IRE1α and the autocrine loop mediated by EREG through ErbB1. IRE1α is a transmembrane protein of the endoplasmic reticulum (ER) and an upstream activator of the JNK to EGFR signaling ①. IRE1 kinase, but not the IRE1 RNase domain, contributes to the high level of EREG production in these cells. Treatment of the cells with the UPR inducers tunicamycin and thapsigargin increases EREG expression using both IRE1α-dependent ① and IRE1α-independent ② pathways. EREG secretion leads to the activation (③ and ④) of EGFR, a protein constitutively expressed by U87 cells. The resulting effect is the autocrine activation of cell proliferation and migration. HB-EGF is another ligand of EGFR and is also expressed by U87 cells. Endogenous expression of EREG and HB-EGF provides a rationale for the consistent level of EGFR autophosphorylation observed under basal conditions. EREG-mediated autocrine loop and sustained activation of EGFR potentially contribute in glioma initiation and progression.