Phosphatidic acid‐PKA signaling regulates p38 and ERK1/2 functions in ligand‐independent EGFR endocytosis. (20th October 2021)

• Record Type: Journal Article
• Authors: Metz, Claudia; Oyanadel, Claudia; Jung, Juan; Retamal, Claudio; Cancino, Jorge; Barra, Jonathan; Venegas, Jaime; Du, Guangwei; Soza, Andrea; González, Alfonso
• Is Part Of: Traffic. Volume 22:Number 10(2021)
• Page Start: 345
• Page End: 361
• Publication Date: 2021-10-20
• Subjects: EGFR -- endocytosis -- ERK1/2 -- MAPK -- p38 -- PDE4 -- phosphatidic acid -- PKA; Biological transport -- Periodicals; 571.6
• DOI: 10.1111/tra.12812
• Languages: English
• ISSNs: 1398-9219

Abstract

Abstract: Ligand‐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. Abstract : Inhibition of basal PKA activity has been described to induce ligand‐independent internalization of EGFR through clathrin‐dependent and clathrin‐independent routes, which here we show to involve downstream activation of p38 and ERK1/2 kinases, respectively. EGFR becomes reversibly arrested at recycling endosomes together with LDLR and TfR. The process can be triggered by phosphatidic acid signaling toward type 4 phosphodiesterases (PDE4), mediating decreases of cAMP levels and PKA activity, with functional and therapeutic implications in cancer.