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: Eileen J. Kennedy, Zheng Cao, James R. Goldenring, Ramona Graves-Deal, Léolène J. Carrington, Jeffrey L. Franklin, Bhuminder Singh, Cunxi Li, Nicholas O. Markham, Robert J. Coffey
Rok vydání: 2019
Předmět:
A‐kinase anchoring protein 12 (AKAP12)
EGFR transactivation
A Kinase Anchor Proteins
Cell Cycle Proteins
Biochemistry
Dinoprostone
Receptor tyrosine kinase
Madin Darby Canine Kidney Cells
transforming growth factor‐α (TGFα)
03 medical and health sciences
Transactivation
Dogs
0302 clinical medicine
Structural Biology
Genetics
Animals
Humans
Epidermal growth factor receptor
Protein kinase A
Molecular Biology
Adaptor Proteins
Signal Transducing
030304 developmental biology
G protein-coupled receptor
0303 health sciences
biology
Calcium-Binding Proteins
Cell Membrane
Original Articles
Cell Biology
Transforming Growth Factor alpha
AKAP12
Cyclic AMP-Dependent Protein Kinases
epidermal growth factor receptor (EGFR)
naked cuticle homolog 2 (NKD2)
Cell biology
ErbB Receptors
Protein Transport
protein kinase A (PKA)
HEK293 Cells
G protein‐coupled receptor (GPCR)
biology.protein
Phosphorylation
Original Article
Caco-2 Cells
030217 neurology & neurosurgery
Signal Transduction
Vasoactive Intestinal Peptide
Transforming growth factor
Zdroj: Traffic (Copenhagen, Denmark)
ISSN: 1600-0854
1398-9219
DOI: 10.1111/tra.12642
Popis: 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 E2 (PGE2) 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 PGE2 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.
Databáze: OpenAIRE
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