PIP3 induces the recycling of receptor tyrosine kinases

Vibor Laketa, Sirus Zarbakhsh, Alexis Traynor-Kaplan, Aidan MacNamara, Devaraj Subramanian, Mateusz Putyrski, Rainer Mueller, André Nadler, Matthias Mentel, Julio Saez-Rodriguez, Rainer Pepperkok, Carsten Schultz

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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 PIP 3-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.

Original languageEnglish (US)
Article numberra5
JournalScience signaling
Volume7
Issue number308
DOIs
StatePublished - Jan 14 2014
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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