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.

Cao Z, Singh B, Li C, Markham NO, Carrington LJ, Franklin JL, Graves-Deal R, Kennedy EJ, Goldenring JR, Coffey RJ
Traffic. 2019 20 (5): 357-368

PMID: 30941853 · PMCID: PMC6618044 · DOI:10.1111/tra.12642

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 (PGE ) 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 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.

MeSH Terms (18)

Adaptor Proteins, Signal Transducing A Kinase Anchor Proteins Animals Caco-2 Cells Calcium-Binding Proteins Cell Cycle Proteins Cell Membrane Cyclic AMP-Dependent Protein Kinases Dinoprostone Dogs ErbB Receptors HEK293 Cells Humans Madin Darby Canine Kidney Cells Protein Transport Signal Transduction Transforming Growth Factor alpha Vasoactive Intestinal Peptide

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