Abstract
BackgroundEndocytosis of activated EGF receptor (EGFR) to specific endocytic compartments is required to terminate EGF signaling. Trafficking of EGFR relies on microtubule tracks that transport the cargo vesicle to their intermediate and final destinations and can be modulated through posttranslational modification of tubulin including acetylation. Na,K-ATPase maintains intracellular sodium homeostasis, functions as a signaling scaffold and interacts with EGFR. Na,K-ATPase also binds to and is regulated by acetylated tubulin but whether there is a functional link between EGFR, Na,K-ATPase and tubulin acetylation is not known.ResultsEGF-induced sodium influx regulates EGFR trafficking through increased microtubule acetylation. Increased sodium influx induced either by sodium ionophores or Na,K-ATPase blockade mimicked the EGF-induced effects on EGFR trafficking through histone deacetylase (HDAC) 6 inactivation and accumulation of acetylated tubulin. In turn, blocking sodium influx reduced tubulin acetylation and EGF-induced EGFR turnover. Knockdown of HDAC6 reversed the effect of sodium influx indicating that HDAC6 is necessary to modulate sodium-dependent tubulin acetylation.ConclusionsThese studies provide a novel regulatory mechanism to attenuate EGFR signaling in which EGF modulates EGFR trafficking through intracellular sodium-mediated HDAC6 inactivation and tubulin acetylation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12860-015-0070-8) contains supplementary material, which is available to authorized users.
Highlights
Endocytosis of activated EGF receptor (EGFR) to specific endocytic compartments is required to terminate EGF signaling
We suggest a novel link between EGFR, sodium influx, microtubule acetylation, and EGFR trafficking and provide evidence that activation of EGFR signaling by its ligand EGF induces a sodium influx thereby increasing tubulin acetylation
Sodium influx induces tubulin acetylation it is well-documented that acetylated tubulin associates with Na,K-ATPase to inhibit its pump function [18], less is known about the effects of reduced Na,K-ATPase function on tubulin acetylation
Summary
Endocytosis of activated EGF receptor (EGFR) to specific endocytic compartments is required to terminate EGF signaling. Trafficking of EGFR relies on microtubule tracks that transport the cargo vesicle to their intermediate and final destinations and can be modulated through posttranslational modification of tubulin including acetylation. Activation of EGF signaling is initiated by interaction of the ligand with a member of the EGFR family. Upon clathrin-dependent endocytosis, endosomal vesicles containing the EGF-EGFR complex are delivered to early and late endosomes through interaction with motor proteins along the microtubule track. Vesicle trafficking along these tracks depends on the motor-cargo complex but can be modulated through posttranslational modification of tubulin, including acetylation [1]
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