Exp Mol Med.  2015 Dec;47(12):e200. 10.1038/emm.2015.101.

The pleckstrin homology domain of phospholipase D1 accelerates EGFR endocytosis by increasing the expression of the Rab5 effector, rabaptin-5

• Park MH
• Choi KY
• Min DS

• KMID: 2359887
• DOI: http://doi.org/10.1038/emm.2015.101

Abstract

Endocytosis is differentially regulated by hypoxia-inducible factor-1alpha (HIF-1alpha) and phospholipase D (PLD). However, the relationship between HIF-1alpha and PLD in endocytosis is unknown. HIF-1alpha 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-1alpha independent of lipase activity via the Rab5-mediated endosome fusion pathway. EGF-induced interaction of PLD1 with HIF-1alpha, PHD and VHL may contribute to EGFR endocytosis. The pleckstrin homology domain (PH) of PLD1 itself promotes degradation of HIF-1alpha, 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-1alpha in the EGFR endocytosis pathway.

MeSH Terms

Animals
Blood Proteins/chemistry/*metabolism
Endocytosis
Female
HEK293 Cells
HT29 Cells
Humans
Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
Mice, Nude
Neoplasms/genetics/metabolism/pathology
Phospholipase D/chemistry/*metabolism
Phosphoproteins/chemistry/*metabolism
Protein Structure, Tertiary
Receptor, Epidermal Growth Factor/*metabolism
Signal Transduction
*Up-Regulation
Vesicular Transport Proteins/*genetics/metabolism
rab5 GTP-Binding Proteins/*metabolism
Blood Proteins
Hypoxia-Inducible Factor 1, alpha Subunit
Phospholipase D
Phosphoproteins
Receptor, Epidermal Growth Factor
rab5 GTP-Binding Proteins
Vesicular Transport Proteins