title: PIP₃ induces the recycling of receptor tyrosine kinases.
abstract: Down-regulation of receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR) is achieved by endocytosis of the receptor followed by degradation or recycling. We demonstrated that in the absence of ligand, increased phosphatidylinositol 3,4,5-trisphosphate (PIP3) concentrations induced clathrin- and dynamin-mediated endocytosis of EGFR but not that of transferrin or G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors. Endocytosis of the receptor in response to binding of EGF resulted in a decrease in the abundance of the EGFR, but PIP3-induced internalization decreased receptor ubiquitination and phosphorylation and resulted in recycling of the receptor to the plasma membrane. An RNA interference (RNAi) screen directed against lipid-binding domain-containing proteins identified polarity complex proteins, including PARD3 (partitioning defective 3), as essential for PIP3-induced receptor tyrosine kinase recycling. Thus, PIP3 and polarity complex proteins regulate receptor tyrosine kinase trafficking, which may enhance cellular responsiveness to growth factors.
authors.affiliation: 1Cell Biology and Biophysics Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstraße 1, 69117 Heidelberg, Germany.
authors.forename: Vibor
authors.initials: V
authors.lastname: Laketa
authors.forename: Sirus
authors.initials: S
authors.lastname: Zarbakhsh
authors.forename: Alexis
authors.initials: A
authors.lastname: Traynor-Kaplan
authors.forename: Aidan
authors.initials: A
authors.lastname: Macnamara
authors.forename: Devaraj
authors.initials: D
authors.lastname: Subramanian
authors.forename: Mateusz
authors.initials: M
authors.lastname: Putyrski
authors.forename: Rainer
authors.initials: R
authors.lastname: Mueller
authors.forename: André
authors.initials: A
authors.lastname: Nadler
authors.forename: Matthias
authors.initials: M
authors.lastname: Mentel
authors.forename: Julio
authors.initials: J
authors.lastname: Saez-Rodriguez
authors.forename: Rainer
authors.initials: R
authors.lastname: Pepperkok
authors.forename: Carsten
authors.initials: C
authors.lastname: Schultz
mesh_terms: D004705:Endocytosis; D006801:Humans; D018129:Phosphatidylinositol Phosphates / Q000502:physiology*; D010766:Phosphorylation; D034622:RNA Interference; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D054875:Ubiquitination
chemical_list: D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D020794:Receptor Protein-Tyrosine Kinases