title: Anticipatory activation of the unfolded protein response by epidermal growth factor is required for immediate early gene expression and cell proliferation.
abstract: The onco-protein epidermal growth factor (EGF) initiates a cascade that includes activation of the ERK and AKT signaling pathways and alters gene expression. We describe a new action of EGF-EGF receptor (EGFR), rapid anticipatory activation of the endoplasmic reticulum stress sensor, the unfolded protein response (UPR). Within 2 min, EGF elicits EGFR dependent activation of phospholipase C γ (PLCγ), producing inositol triphosphate (IP3), which binds to IP3 receptor (IP3R), opening the endoplasmic reticulum IP3R Ca(2+) channels, resulting in increased intracellular Ca(2+). This calcium release leads to transient and moderate activation of the IRE1α and ATF6α arms of the UPR, resulting in induction of BiP chaperone. Knockdown or inhibition of EGFR, PLCγ or IP3R blocks the increase in intracellular Ca(2+). While blocking the increase in intracellular Ca(2+) by locking the IP3R calcium channel with 2-APB had no effect on EGF activation of the ERK or AKT signaling pathways, it abolished the rapid EGF-mediated induction and repression of gene expression. Knockdown of ATF6α or XBP1, which regulate UPR-induced chaperone production, inhibited EGF stimulated cell proliferation. Supporting biological relevance, increased levels of EGF receptor during tumor progression were correlated with increased expression of the UPR gene signature. Anticipatory activation of the UPR is a new role for EGF. Since UPR activation occurs in <2 min, it is an initial cell response when EGF binds EGFR.
authors.affiliation: Department of Biochemistry, University of Illinois, Urbana, IL, 61801, USA.
authors.forename: Liqun
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Biochemistry, University of Illinois, Urbana, IL, 61801, USA; College of Medicine, University of Illinois, USA.
authors.forename: Neal
authors.initials: N
authors.lastname: Andruska
authors.affiliation: Department of Biochemistry, University of Illinois, Urbana, IL, 61801, USA.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Biochemistry, University of Illinois, Urbana, IL, 61801, USA; University of Illinois Cancer Center, USA; College of Medicine, University of Illinois, USA. Electronic address: djshapir@life.illinois.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Shapiro
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017781:Genes, Immediate-Early / Q000187:drug effects*; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects*
chemical_list: D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D002118:Calcium
keywords: Breast cancer; Calcium; Epidermal growth factor (EGF); Gene regulation; Unfolded protein response (UPR)