title: GABARAPL1 is required for increased EGFR membrane expression during hypoxia.
abstract: OBJECTIVE
  The epidermal growth factor receptor (EGFR) is overexpressed, amplified or mutated in various human epithelial tumors and hypoxia is a common feature of solid tumors. Both EGFR and hypoxia are associated with therapy resistance and poor treatment outcome. To survive hypoxia, cells adapt by activation of hypoxia responsive pathways and expression of hypoxia-induced plasma membrane proteins. We observed that GABAA receptor associated protein like1 (GABARAPL1) and plasma membrane expression of EGFR were increased during hypoxia. Here we explored the role of the GABARAPL1 in EGFR membrane expression during hypoxia.
  
  
  METHODS
  Quantitative qPCR, immunoblot analysis, flow cytometry and cytochemistry were used to assess this interplay.
  
  
  RESULTS
  GABARAPL1 mRNA and protein levels are increased during hypoxia in vitro and correlate with tumor hypoxia in a panel of primary HNSCC xenografts. High GABARAPL1 mRNA is associated with poor outcome of HNSCC patients. During hypoxia, EGFR membrane expression is increased and GABARAPL1 and EGFR colocalize at the plasma membrane. GABARAPL1 knockdown inhibits EGFR membrane expression during hypoxia.
  
  
  CONCLUSIONS
  GABARAPL1 is required for increased membrane expression of EGFR during hypoxia, suggesting a role for GABARAPL1 in the trafficking of these membrane proteins.
authors.affiliation: Maastricht Radiation Oncology (MaastRO) lab, GROW - School for Oncology and Developmental Biology, Maastricht University, The Netherlands.
authors.forename: Tom G
authors.initials: TG
authors.lastname: Keulers
authors.affiliation: Maastricht Radiation Oncology (MaastRO) lab, GROW - School for Oncology and Developmental Biology, Maastricht University, The Netherlands.
authors.forename: Marco B E
authors.initials: MB
authors.lastname: Schaaf
authors.affiliation: Maastricht Radiation Oncology (MaastRO) lab, GROW - School for Oncology and Developmental Biology, Maastricht University, The Netherlands.
authors.forename: Hanneke J M
authors.initials: HJ
authors.lastname: Peeters
authors.affiliation: Maastricht Radiation Oncology (MaastRO) lab, GROW - School for Oncology and Developmental Biology, Maastricht University, The Netherlands.
authors.forename: Kim G M
authors.initials: KG
authors.lastname: Savelkouls
authors.affiliation: Maastricht Radiation Oncology (MaastRO) lab, GROW - School for Oncology and Developmental Biology, Maastricht University, The Netherlands.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Vooijs
authors.affiliation: Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Bussink
authors.affiliation: Maastricht Radiation Oncology (MaastRO) lab, GROW - School for Oncology and Developmental Biology, Maastricht University, The Netherlands.
authors.forename: Barry
authors.initials: B
authors.lastname: Jutten
authors.affiliation: Maastricht Radiation Oncology (MaastRO) lab, GROW - School for Oncology and Developmental Biology, Maastricht University, The Netherlands. Electronic address: Kasper.Rouschop@maastrichtuniversity.nl.
authors.forename: Kasper M A
authors.initials: KM
authors.lastname: Rouschop
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000963:Antimetabolites / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D004318:Doxycycline / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D008869:Microtubule-Associated Proteins / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000963:Antimetabolites; C430503:GABARAPL1 protein, human; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; C512478:EGFR protein, human; D066246:ErbB Receptors; D004318:Doxycycline
keywords: Autophagy; EGFR; GABARAPL1; Hypoxia; Receptor trafficking; UPR