TY - JOUR
T1 - PIP3 induces the recycling of receptor tyrosine kinases
AU - Laketa, Vibor
AU - Zarbakhsh, Sirus
AU - Traynor-Kaplan, Alexis
AU - MacNamara, Aidan
AU - Subramanian, Devaraj
AU - Putyrski, Mateusz
AU - Mueller, Rainer
AU - Nadler, André
AU - Mentel, Matthias
AU - Saez-Rodriguez, Julio
AU - Pepperkok, Rainer
AU - Schultz, Carsten
PY - 2014/1/14
Y1 - 2014/1/14
N2 - 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.
AB - 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.
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U2 - 10.1126/scisignal.2004532
DO - 10.1126/scisignal.2004532
M3 - Article
C2 - 24425787
AN - SCOPUS:84892647719
SN - 1945-0877
VL - 7
JO - Science signaling
JF - Science signaling
IS - 308
M1 - ra5
ER -