title: The pleckstrin homology domain of phospholipase D1 accelerates EGFR endocytosis by increasing the expression of the Rab5 effector, rabaptin-5.
abstract: Endocytosis is differentially regulated by hypoxia-inducible factor-1α (HIF-1α) and phospholipase D (PLD). However, the relationship between HIF-1α and PLD in endocytosis is unknown. HIF-1α is degraded through the prolyl hydroxylase (PHD)/von Hippel-Lindau (VHL) ubiquitination pathway in an oxygen-dependent manner. Here, we show that PLD1 recovers the decrease in epidermal growth factor receptor (EGFR) endocytosis induced by HIF-1α independent of lipase activity via the Rab5-mediated endosome fusion pathway. EGF-induced interaction of PLD1 with HIF-1α, PHD and VHL may contribute to EGFR endocytosis. The pleckstrin homology domain (PH) of PLD1 itself promotes degradation of HIF-1α, then accelerates EGFR endocytosis via upregulation of rabaptin-5 and suppresses tumor progression. These findings reveal a novel role of the PLD1-PH domain as a positive regulator of endocytosis and provide a link between PLD1 and HIF-1α in the EGFR endocytosis pathway.
authors.affiliation: Department of Molecular Biology, College of Natural Science, Pusan National University, Busan, Republic of Korea.
authors.forename: Mi Hee
authors.initials: MH
authors.lastname: Park
authors.affiliation: Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.|Translational Research Center for Protein Function Control, Yonsei University, Seoul, Republic of Korea.
authors.forename: Kang-Yell
authors.initials: KY
authors.lastname: Choi
authors.affiliation: Department of Molecular Biology, College of Natural Science, Pusan National University, Busan, Republic of Korea.|Translational Research Center for Protein Function Control, Yonsei University, Seoul, Republic of Korea.|Genetic Engineering Institute, Pusan National University, Busan, Republic of Korea.
authors.forename: Do Sik
authors.initials: do S
authors.lastname: Min
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000737:chemistry / Q000378:metabolism*; D004705:Endocytosis; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010739:Phospholipase D / Q000737:chemistry / Q000378:metabolism*; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D015854:Up-Regulation; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D001798:Blood Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010750:Phosphoproteins; C097227:RABEP1 protein, human; D033921:Vesicular Transport Proteins; C039077:platelet protein P47; C512478:EGFR protein, human; D066246:ErbB Receptors; D010739:Phospholipase D; C106801:phospholipase D1; D020696:rab5 GTP-Binding Proteins