title: Hypoxia promotes ligand-independent EGF receptor signaling via hypoxia-inducible factor-mediated upregulation of caveolin-1.
abstract: Caveolin-1 (CAV1) is an essential structural constituent of caveolae, specialized lipid raft microdomains on the cell membrane involved in endocytosis and signal transduction, which are inexplicably deregulated and are associated with aggressiveness in numerous cancers. Here we identify CAV1 as a direct transcriptional target of oxygen-labile hypoxia-inducible factor 1 and 2 that accentuates the formation of caveolae, leading to increased dimerization of EGF receptor within the confined surface area of caveolae and its subsequent phosphorylation in the absence of ligand. Hypoxia-inducible factor-dependent up-regulation of CAV1 enhanced the oncogenic potential of tumor cells by increasing the cell proliferative, migratory, and invasive capacities. These results support a concept in which a crisis in oxygen availability or a tumor exhibiting hypoxic signature triggers caveolae formation that bypasses the requirement for ligand engagement to initiate receptor activation and the critical downstream adaptive signaling during a period when ligands required to activate these receptors are limited or are not yet available.
authors.affiliation: Department of Laboratory Medicine and Pathobiology,  University of Toronto, Toronto, ON,  Canada M5S 1A8.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Olga
authors.initials: O
authors.lastname: Roche
authors.forename: Chaoying
authors.initials: C
authors.lastname: Xu
authors.forename: Eduardo H
authors.initials: EH
authors.lastname: Moriyama
authors.forename: Pardeep
authors.initials: P
authors.lastname: Heir
authors.forename: Jacky
authors.initials: J
authors.lastname: Chung
authors.forename: Frederik C
authors.initials: FC
authors.lastname: Roos
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Chen
authors.forename: Greg
authors.initials: G
authors.lastname: Finak
authors.forename: Michael
authors.initials: M
authors.lastname: Milosevic
authors.forename: Brian C
authors.initials: BC
authors.lastname: Wilson
authors.forename: Bin Tean
authors.initials: BT
authors.lastname: Teh
authors.forename: Morag
authors.initials: M
authors.lastname: Park
authors.forename: Meredith S
authors.initials: MS
authors.lastname: Irwin
authors.forename: Michael
authors.initials: M
authors.lastname: Ohh
mesh_terms: D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D021941:Caveolae / Q000378:metabolism / Q000648:ultrastructure; D051242:Caveolin 1 / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017124:Conserved Sequence / Q000235:genetics; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D008024:Ligands; D020935:MAP Kinase Signaling System; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D012319:RNA Polymerase II / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction; D014158:Transcription, Genetic; D015854:Up-Regulation; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051242:Caveolin 1; D066246:ErbB Receptors; D051793:Hypoxia-Inducible Factor 1; D008024:Ligands; D012319:RNA Polymerase II; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497446:VHL protein, human