Phosphatidic acid induces ligand-independent epidermal growth factor receptor endocytic traffic through PDE4 activation

Andrés Norambuena, Claudia Metz, Juan E. Jung, Antonia Silva, Carolina Otero, Jorge Cancino, Claudio Retamal, Juan C. Valenzuela, Andrea Soza, Alfonso González

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

Abstract

Endocytosis modulates EGFR function by compartmentalizing and attenuating or enhancing its ligand-induced signaling. Here we show that it can also control the cell surface versus intracellular distribution of empty/inactive EGFR. Our previous observation that PKA inhibitors induce EGFR internalization prompted us to test phosphatidic acid (PA) generated by phospholipase D (PLD) as an endogenous down-regulator of PKA activity, which activates rolipram-sensitive type 4 phosphodiesterases (PDE4) that degrade cAMP. We found that inhibition of PA hydrolysis by propranolol, in the absence of ligand, provokes internalization of inactive (neither tyrosine-phosphorylated nor ubiquitinated) EGFR, accompanied by a transient increase in PA levels and PDE4s activity. This EGFR internalization is mimicked by PA micelles and is strongly counteracted by PLD2 silencing, rolipram or forskolin treatment, and PKA overexpression. Accelerated EGFR endocytosis seems to be mediated by clathrin-dependent and -independent pathways, leading to receptor accumulation in juxtanuclear recycling endosomes, also due to a decreased recycling. Internalized EGFR can remain intracellular without degradation for several hours or return rapidly to the cell surface upon discontinuation of the stimulus. This novel regulatory mechanism of EGFR, also novel function of signaling PA, can transmodulate receptor accessibility in response to heterologous stimuli.

Original languageEnglish
Pages (from-to)2916-2929
Number of pages14
JournalMolecular Biology of the Cell
Volume21
Issue number16
DOIs
Publication statusPublished - 15 Aug 2010

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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