New mode of EGF receptor transactivation: regulated ligand delivery

Abstract

EGF receptor (EGFR) transactivation is achieved by GPCR‐mediated, metalloprotease‐dependent cell surface cleavage of an EGFR ligand whereupon soluble ligand binds and activates the receptor. NKD2, a basolateral sorting adaptor for the EGFR ligand TGF‐α, is phosphorylated at S223 by protein kinase A (PKA) in cells stimulated by forskolin or the GPCR agonist VIP. This phosphorylation stabilizes NKD2, ensuring efficient delivery of TGF‐α to the cell surface for its subsequent cleavage by metalloproteases. PKA‐mediated NKD2 phosphorylation is facilitated by smAKAP, an A Kinase Anchoring Protein with no known previous function. Thus, PKA‐mediated efficient delivery of TGF‐α to the cell surfaces in response to GPCR agonist stimulation represents a new mode of EGFR transactivation that occurs proximal to metalloprotease‐activated ligand cleavage.