Interaction of the human prostacyclin receptor with the PDZ adapter protein PDZK : role in endothelial cell migration and angiogenesis

Prostacyclin is increasingly implicated in re-endothelialization and angiogenesis but through largely unknown mechanisms. Herein, the HDL scavenger receptor class B, type 1 (SR-B1) adapter protein PDZ domain-containing protein 1 (PDZK1) was identified as an interactant of the human prostacyclin receptor (hIP) involving a Class I PDZ ligand at its carboxyl-terminus and PDZ domains 1, 3 and 4 of PDZK1. While the interaction is constitutive, it may be dynamically regulated following cicaprost-activation of the hIP through a mechanism involving cAMP-dependent protein kinase (PK)A-phosphorylation of PDZK1 at Ser505. While PDZK1 did not increase overall levels of the hIP, it increased its functional expression at the cell surface enhancing ligand binding and cicaprost-induced cAMP generation. Consistent with its role in re-endothelialization and angiogenesis, cicaprost-activation of the hIP increased endothelial cell migration and tube formation/in vitro angiogenesis, effects completely abrogated by the specific IP antagonist RO1138452. Furthermore, similar to HDL/SR-B1, siRNA-targeted disruption of PDZK1 abolished cicaprost-mediated endothelial responses but did not affect VEGF-responses. Considering the essential role played by prostacyclin throughout the cardiovascular system, identification of PDZK1 as a functional interactant of the hIP sheds significant mechanistic insights into the protective roles of these key players, and potentially HDL/SR-B1, within the vascular endothelium.