Phosphatidic Acid Induces Ligand-independent Epidermal Growth Factor Receptor Endocytic Traffic through PDE4 Activation

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dc.contributor.authorNorambuena, Andres
dc.contributor.authorMetz, Claudia
dc.contributor.authorJung, Juan E.
dc.contributor.authorSilva, Antonia
dc.contributor.authorOtero, Carolina
dc.contributor.authorCancino, Jorge
dc.contributor.authorRetamal, Claudio
dc.contributor.authorValenzuela, Juan C.
dc.contributor.authorSoza, Andrea
dc.contributor.authorGonzalez, Alfonso
dc.date.accessioned2024-01-10T13:52:05Z
dc.date.available2024-01-10T13:52:05Z
dc.date.issued2010
dc.description.abstractEndocytosis 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.
dc.description.funderFondo Nacional de Areas Prioritarias (FONDAP)
dc.description.funderComision de Investigacion Cientifica y Tecnologica (CONICYT)
dc.description.funderFONDECYT
dc.description.funderPontificia Universidad Catolica de Chile
dc.description.funderMinisterio de Planificacion y Cooperacion de Chile
dc.fechaingreso.objetodigital2024-04-30
dc.format.extent14 páginas
dc.fuente.origenWOS
dc.identifier.doi10.1091/mbc.E10-02-0167
dc.identifier.eissn1939-4586
dc.identifier.issn1059-1524
dc.identifier.pubmedidMEDLINE:20554760
dc.identifier.urihttps://doi.org/10.1091/mbc.E10-02-0167
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/79643
dc.identifier.wosidWOS:000280875200010
dc.information.autorucMedicina;González A;S/I;52306
dc.information.autorucCiencias Biológicas;Jung JE;S/I;1204
dc.information.autorucMedicina;Metz C;S/I;65286
dc.information.autorucAgronomía e Ing. Forestal;Norambuena A;S/I;94539
dc.information.autorucCiencias Biológicas;Silva A;S/I;3863
dc.information.autorucMedicina;Soza A;S/I;129570
dc.issue.numero16
dc.language.isoen
dc.nota.accesocontenido parcial
dc.pagina.final2929
dc.pagina.inicio2916
dc.publisherAMER SOC CELL BIOLOGY
dc.revistaMOLECULAR BIOLOGY OF THE CELL
dc.rightsacceso restringido
dc.subjectPROTEIN-KINASE-A
dc.subjectCYCLIC-NUCLEOTIDE PHOSPHODIESTERASE
dc.subjectPHOSPHOLIPASE-D
dc.subjectEGF-RECEPTOR
dc.subjectPLASMA-MEMBRANE
dc.subjectCLATHRIN
dc.subjectDOMAIN
dc.subjectINTERNALIZATION
dc.subjectRECRUITMENT
dc.subjectBINDING
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titlePhosphatidic Acid Induces Ligand-independent Epidermal Growth Factor Receptor Endocytic Traffic through PDE4 Activation
dc.typeartículo
dc.volumen21
sipa.codpersvinculados52306
sipa.codpersvinculados1204
sipa.codpersvinculados65286
sipa.codpersvinculados94539
sipa.codpersvinculados3863
sipa.codpersvinculados129570
sipa.indexWOS
sipa.indexScopus
sipa.trazabilidadCarga SIPA;09-01-2024
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