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

Resultado de la investigación: Article

18 Citas (Scopus)

Resumen

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.

Idioma originalEnglish
Páginas (desde-hasta)2916-2929
Número de páginas14
PublicaciónMolecular Biology of the Cell
Volumen21
N.º16
DOI
EstadoPublished - 15 ago 2010

Huella dactilar

Phosphatidic Acids
Epidermal Growth Factor Receptor
Ligands
Type 4 Cyclic Nucleotide Phosphodiesterase
Rolipram
Endocytosis
Phospholipase D
Clathrin
Endosomes
Recycling
Micelles
Colforsin
Propranolol
Tyrosine
Hydrolysis

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Citar esto

Norambuena, Andrés ; Metz, Claudia ; Jung, Juan E. ; Silva, Antonia ; Otero, Carolina ; Cancino, Jorge ; Retamal, Claudio ; Valenzuela, Juan C. ; Soza, Andrea ; González, Alfonso. / Phosphatidic acid induces ligand-independent epidermal growth factor receptor endocytic traffic through PDE4 activation. En: Molecular Biology of the Cell. 2010 ; Vol. 21, N.º 16. pp. 2916-2929.
@article{0debc41baa314c91b7e30a5e8238399a,
title = "Phosphatidic acid induces ligand-independent epidermal growth factor receptor endocytic traffic through PDE4 activation",
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.",
author = "Andr{\'e}s Norambuena and Claudia Metz and Jung, {Juan E.} and Antonia Silva and Carolina Otero and Jorge Cancino and Claudio Retamal and Valenzuela, {Juan C.} and Andrea Soza and Alfonso Gonz{\'a}lez",
year = "2010",
month = "8",
day = "15",
doi = "10.1091/mbc.E10-02-0167",
language = "English",
volume = "21",
pages = "2916--2929",
journal = "Molecular Biology of the Cell",
issn = "1059-1524",
publisher = "American Society for Cell Biology",
number = "16",

}

Norambuena, A, Metz, C, Jung, JE, Silva, A, Otero, C, Cancino, J, Retamal, C, Valenzuela, JC, Soza, A & González, A 2010, 'Phosphatidic acid induces ligand-independent epidermal growth factor receptor endocytic traffic through PDE4 activation', Molecular Biology of the Cell, vol. 21, n.º 16, pp. 2916-2929. https://doi.org/10.1091/mbc.E10-02-0167

Phosphatidic acid induces ligand-independent epidermal growth factor receptor endocytic traffic through PDE4 activation. / Norambuena, Andrés; Metz, Claudia; Jung, Juan E.; Silva, Antonia; Otero, Carolina; Cancino, Jorge; Retamal, Claudio; Valenzuela, Juan C.; Soza, Andrea; González, Alfonso.

En: Molecular Biology of the Cell, Vol. 21, N.º 16, 15.08.2010, p. 2916-2929.

Resultado de la investigación: Article

TY - JOUR

T1 - Phosphatidic acid induces ligand-independent epidermal growth factor receptor endocytic traffic through PDE4 activation

AU - Norambuena, Andrés

AU - Metz, Claudia

AU - Jung, Juan E.

AU - Silva, Antonia

AU - Otero, Carolina

AU - Cancino, Jorge

AU - Retamal, Claudio

AU - Valenzuela, Juan C.

AU - Soza, Andrea

AU - González, Alfonso

PY - 2010/8/15

Y1 - 2010/8/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77955590833&partnerID=8YFLogxK

U2 - 10.1091/mbc.E10-02-0167

DO - 10.1091/mbc.E10-02-0167

M3 - Article

C2 - 20554760

AN - SCOPUS:77955590833

VL - 21

SP - 2916

EP - 2929

JO - Molecular Biology of the Cell

JF - Molecular Biology of the Cell

SN - 1059-1524

IS - 16

ER -