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Sci. Signal., 14 January 2014
Vol. 7, Issue 308, p. ra5
[DOI: 10.1126/scisignal.2004532]

RESEARCH ARTICLES

PIP3 Induces the Recycling of Receptor Tyrosine Kinases

Vibor Laketa1, Sirus Zarbakhsh1, Alexis Traynor-Kaplan2,3, Aidan MacNamara4, Devaraj Subramanian1, Mateusz Putyrski1, Rainer Mueller1, André Nadler1, Matthias Mentel1, Julio Saez-Rodriguez4, Rainer Pepperkok1, and Carsten Schultz1*

1 Cell Biology and Biophysics Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstraße 1, 69117 Heidelberg, Germany.
2 ATK Innovation Analytics & Discovery, Southeast 108th Street, North Bend, WA 98045, USA.
3 Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, WA 98195–6424, USA.
4 EMBL European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.

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.

* Corresponding author. E-mail: schultz{at}embl.de

Citation: V. Laketa, S. Zarbakhsh, A. Traynor-Kaplan, A. MacNamara, D. Subramanian, M. Putyrski, R. Mueller, A. Nadler, M. Mentel, J. Saez-Rodriguez, R. Pepperkok, C. Schultz, PIP3 Induces the Recycling of Receptor Tyrosine Kinases. Sci. Signal. 7, ra5 (2014).

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