Regulation of endocytosis via the oxygen-sensing pathway.
Tumor hypoxia is associated with disease progression, resistance to conventional cancer therapies and poor prognosis. Hypoxia, by largely unknown mechanisms, leads to deregulated accumulation of and signaling via receptor tyrosine kinases (RTKs) that are critical for driving oncogenesis. Here, we show that hypoxia or loss of von Hippel-Lindau protein--the principal negative regulator of hypoxia-inducible factor (HIF)--prolongs the activation of epidermal growth factor receptor that is attributable to lengthened receptor half-life and retention in the endocytic pathway. The deceleration in endocytosis is due to the attenuation of Rab5-mediated early endosome fusion via HIF-dependent downregulation of a critical Rab5 effector, rabaptin-5, at the level of transcription. Primary kidney and breast tumors with strong hypoxic signatures show significantly lower expression of rabaptin-5 RNA and protein. These findings reveal a general role of the oxygen-sensing pathway in endocytosis and support a model in which tumor hypoxia or oncogenic activation of HIF prolongs RTK-mediated signaling by delaying endocytosis-mediated deactivation of receptors.
Wang
Yi
Y
Department of Laboratory Medicine and Pathobiology, St. Michael's Hospital, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
Roche
Olga
O
Yan
Mathew S
MS
Finak
Greg
G
Evans
Andrew J
AJ
Metcalf
Julie L
JL
Hast
Bridgid E
BE
Hanna
Sara C
SC
Wondergem
Bill
B
Furge
Kyle A
KA
Irwin
Meredith S
MS
Kim
William Y
WY
Teh
Bin T
BT
Grinstein
Sergio
S
Park
Morag
M
Marsden
Philip A
PA
Ohh
Michael
M
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004705:Endocytosis; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D008969:Molecular Sequence Data; D010100:Oxygen / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000502:physiology; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000502:physiology
C097227:RABEP1 protein, human; D033921:Vesicular Transport Proteins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D020794:Receptor Protein-Tyrosine Kinases; C497446:VHL protein, human; D010100:Oxygen