title: Tid1-L inhibits EGFR signaling in lung adenocarcinoma by enhancing EGFR Ubiquitinylation and degradation.
abstract: Tid1 (DNAJA3), a DnaJ cochaperone, may promote degradation of oncogenic kinases. Tid1 has 2 isoforms, Tid1-L and Tid1-S, that may function differently. In this study, we investigated the role of the Tid1 isoforms in regulating EGF receptor (EGFR) signaling and lung cancer progression. We found that both Tid1-L and Tid1-S expressions were reduced in patients with non-small cell lung cancer compared with normal counterparts. Tid1-L expression correlated inversely with EGFR expression. Low Tid1-L/high EGFR expression predicted poor overall survival in patients with lung adenocarcinoma. Tid1-L overexpression in lung cancer cells attenuated EGFR signaling and inhibited cell proliferation, colony formation, and tumor growth in subcutaneous and orthotropic xenograft models. Conversely, depletion of Tid1 restored EGFR signaling and increased cell proliferation and colony formation. Tid1-L, but not Tid1-S, interacted with EGFR/HSP70/HSP90 through the DnaJ domain, counteracting the EGFR regulatory function of HSP90 by causing EGFR ubiquitinylation and proteasomal degradation. Tid1-L inhibited EGFR signaling even more than the HSP90 inhibitor 17-allylamino-demethoxy geldanamycin. We concluded that Tid1-L acted as a tumor suppressor by inhibiting EGFR signaling through interaction with EGFR/HSP70/HSP90 and enhancing EGFR ubiquitinylation and degradation.
authors.affiliation: Department of Nutrition and Health Sciences, Chang Gung University of Science and Technology, Taoyuan, Taiwan.
authors.forename: Chi-Yuan
authors.initials: CY
authors.lastname: Chen
authors.forename: Chia-Ing
authors.initials: CI
authors.lastname: Jan
authors.forename: Jeng-Fan
authors.initials: JF
authors.lastname: Lo
authors.forename: Shuenn-Chen
authors.initials: SC
authors.lastname: Yang
authors.forename: Yih-Leong
authors.initials: YL
authors.lastname: Chang
authors.forename: Szu-Hua
authors.initials: SH
authors.lastname: Pan
authors.forename: Wen-Lung
authors.initials: WL
authors.lastname: Wang
authors.forename: Tse-Ming
authors.initials: TM
authors.lastname: Hong
authors.forename: Pan-Chyr
authors.initials: PC
authors.lastname: Yang
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality; D000077192:Adenocarcinoma of Lung; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004815:Epidermal Growth Factor / Q000502:physiology; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D050956:HSP40 Heat-Shock Proteins / Q000737:chemistry / Q000502:physiology*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D015999:Multivariate Analysis; D009368:Neoplasm Transplantation; D025821:Polyubiquitin / Q000378:metabolism; D020033:Protein Isoforms / Q000737:chemistry / Q000502:physiology; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D015398:Signal Transduction; D054875:Ubiquitination
chemical_list: C120664:DNAJA3 protein, human; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D020033:Protein Isoforms; D025821:Polyubiquitin; D004815:Epidermal Growth Factor; D066246:ErbB Receptors