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dc.contributor.author Norambuena, Andrés
dc.contributor.author Metz, Claudia
dc.contributor.author Jung, Juan E.
dc.contributor.author Silva, Antonia
dc.contributor.author Otero, Carolina
dc.contributor.author Cancino, Jorge
dc.contributor.author Retamal, Claudio
dc.contributor.author Valenzuela, Juan C.
dc.contributor.author Soza, Andrea
dc.contributor.author González, Alfonso
dc.date.accessioned 2024-09-26T00:32:17Z
dc.date.available 2024-09-26T00:32:17Z
dc.date.issued 2010-08-15
dc.identifier.issn 1059-1524
dc.identifier.uri https://repositorio.uss.cl/handle/uss/12513
dc.description.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. en
dc.language.iso eng
dc.relation.ispartof vol. 21 Issue: no. 16 Pages: 2916-2929
dc.source Molecular Biology of the Cell
dc.title Phosphatidic acid induces ligand-independent epidermal growth factor receptor endocytic traffic through PDE4 activation en
dc.type Artículo
dc.identifier.doi 10.1091/mbc.E10-02-0167
dc.publisher.department Facultad de Medicina y Ciencia


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