Regulation of endocytosis via the oxygen-sensing pathway

摘要: Tumor hypoxia is associated with disease progression, resistance to conventional cancer therapies and poor prognosis. Hypoxia, by largely unknown mechanisms, leads deregulated accumulation of signaling via receptor tyrosine kinases (RTKs) that are critical for driving oncogenesis. Here, we show or loss von Hippel-Lindau protein--the principal negative regulator hypoxia-inducible factor (HIF)--prolongs the activation epidermal growth attributable lengthened half-life retention in endocytic pathway. The deceleration endocytosis due attenuation Rab5-mediated early endosome fusion HIF-dependent downregulation a Rab5 effector, rabaptin-5, at level transcription. Primary kidney breast tumors strong hypoxic signatures significantly lower expression rabaptin-5 RNA protein. These findings reveal general role oxygen-sensing pathway support model which tumor oncogenic HIF prolongs RTK-mediated delaying endocytosis-mediated deactivation receptors.