Phosphatidic acid-PKA signaling regulates p38 and ERK1/2 functions in ligand-independent EGFR endocytosis

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dc.contributor.authorMetz, Claudia
dc.contributor.authorOyanadel, Claudia
dc.contributor.authorJung, Juan
dc.contributor.authorRetamal, Claudio
dc.contributor.authorCancino, Jorge
dc.contributor.authorBarra, Jonathan
dc.contributor.authorVenegas, Jaime
dc.contributor.authorDu, Guangwei
dc.contributor.authorSoza, Andrea
dc.contributor.authorGonzalez, Alfonso
dc.date.accessioned2025-01-20T22:06:19Z
dc.date.available2025-01-20T22:06:19Z
dc.date.issued2021
dc.description.abstractLigand-independent epidermal growth factor receptor (EGFR) endocytosis is inducible by a variety of stress conditions converging upon p38 kinase. A less known pathway involves phosphatidic acid (PA) signaling toward the activation of type 4 phosphodiesterases (PDE4) that decrease cAMP levels and protein kinase A (PKA) activity. This PA/PDE4/PKA pathway is triggered with propranolol used to inhibit PA hydrolysis and induces clathrin-dependent and clathrin-independent endocytosis, followed by reversible accumulation of EGFR in recycling endosomes. Here we give further evidence of this signaling pathway using biosensors of PA, cAMP, and PKA in live cells and then show that it activates p38 and ERK1/2 downstream the PKA inhibition. Clathrin-silencing and IN/SUR experiments involved the activity of p38 in the clathrin-dependent route, while ERK1/2 mediates clathrin-independent EGFR endocytosis. The PA/PDE4/PKA pathway selectively increases the EGFR endocytic rate without affecting LDLR and TfR constitute endocytosis. This selectiveness is probably because of EGFR phosphorylation, as detected in Th1046/1047 and Ser669 residues. The EGFR accumulates at perinuclear recycling endosomes colocalizing with TfR, fluorescent transferrin, and Rab11, while a small proportion distributes to Alix-endosomes. A non-selective recycling arrest includes LDLR and TfR in a reversible manner. The PA/PDE4/PKA pathway involving both p38 and ERK1/2 expands the possibilities of EGFR transmodulation and interference in cancer.
dc.fuente.origenWOS
dc.identifier.doi10.1111/tra.12812
dc.identifier.eissn1600-0854
dc.identifier.issn1398-9219
dc.identifier.urihttps://doi.org/10.1111/tra.12812
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/94202
dc.identifier.wosidWOS:000709073700003
dc.issue.numero10
dc.language.isoen
dc.pagina.final361
dc.pagina.inicio345
dc.revistaTraffic
dc.rightsacceso restringido
dc.subjectEGFR
dc.subjectendocytosis
dc.subjectERK1
dc.subject2
dc.subjectMAPK
dc.subjectp38
dc.subjectPDE4
dc.subjectphosphatidic acid
dc.subjectPKA
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titlePhosphatidic acid-PKA signaling regulates p38 and ERK1/2 functions in ligand-independent EGFR endocytosis
dc.typeartículo
dc.volumen22
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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