Protein kinase A-mediated phosphorylation of naked cuticle homolog 2 stimulates cell-surface delivery of transforming growth factor-α for epidermal growth factor receptor transactivation.

Autor: Cao Z; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee., Singh B; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee.; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee., Li C; Jiaen Genetics Laboratory, Beijing Jiaen Hospital, Beijing, China.; Genetics Center, Shenzhen IVF Gynecology Hospital, Shenzhen, China., Markham NO; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee., Carrington LJ; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee., Franklin JL; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee.; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee.; Department of Medicine, Veterans Affairs Medical Center, Nashville, Tennessee., Graves-Deal R; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee., Kennedy EJ; Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia., Goldenring JR; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee.; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee.; Department of Medicine, Veterans Affairs Medical Center, Nashville, Tennessee.; Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee., Coffey RJ; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee.; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee.; Department of Medicine, Veterans Affairs Medical Center, Nashville, Tennessee.
Jazyk: angličtina
Zdroj: Traffic (Copenhagen, Denmark) [Traffic] 2019 May; Vol. 20 (5), pp. 357-368.
DOI: 10.1111/tra.12642
Abstrakt: The classic mode of G protein-coupled receptor (GPCR)-mediated transactivation of the receptor tyrosine kinase epidermal growth factor receptor (EGFR) transactivation occurs via matrix metalloprotease (MMP)-mediated cleavage of plasma membrane-anchored EGFR ligands. Herein, we show that the Gαs-activating GPCR ligands vasoactive intestinal peptide (VIP) and prostaglandin E 2 (PGE 2 ) transactivate EGFR through increased cell-surface delivery of the EGFR ligand transforming growth factor-α (TGFα) in polarizing madin-darby canine kidney (MDCK) and Caco-2 cells. This is achieved by PKA-mediated phosphorylation of naked cuticle homolog 2 (NKD2), previously shown to bind TGFα and direct delivery of TGFα-containing vesicles to the basolateral surface of polarized epithelial cells. VIP and PGE 2 rapidly activate protein kinase A (PKA) that then phosphorylates NKD2 at Ser-223, a process that is facilitated by the molecular scaffold A-kinase anchoring protein 12 (AKAP12). This phosphorylation stabilized NKD2, ensuring efficient cell-surface delivery of TGFα and increased EGFR activation. Thus, GPCR-triggered, PKA/AKAP12/NKD2-regulated targeting of TGFα to the cell surface represents a new mode of EGFR transactivation that occurs proximal to ligand cleavage by MMPs.
(© 2019 The Authors. Traffic published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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