Interaction of the human prostacyclin receptor with the PDZ adapter protein PDZK1: role in endothelial cell migration and angiogenesis.
Prostacyclin is increasingly implicated in re-endothelialization and angiogenesis but through largely unknown mechanisms. Herein the high-density lipoprotein (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. Although 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 Ser-505. Although 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, small interfering RNA (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.
Mesh Terms:
Animals, Antineoplastic Agents, Benzyl Compounds, Carrier Proteins, Cell Membrane, Cell Movement, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Endothelial Cells, Endothelium, Vascular, Epoprostenol, Gene Expression Regulation, HEK293 Cells, Humans, Imidazoles, Lipoproteins, HDL, Mice, Mice, Knockout, Neovascularization, Physiologic, PDZ Domains, Phosphorylation, Protein Binding, Protein Structure, Tertiary, Receptors, Prostaglandin, Signal Transduction
Animals, Antineoplastic Agents, Benzyl Compounds, Carrier Proteins, Cell Membrane, Cell Movement, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Endothelial Cells, Endothelium, Vascular, Epoprostenol, Gene Expression Regulation, HEK293 Cells, Humans, Imidazoles, Lipoproteins, HDL, Mice, Mice, Knockout, Neovascularization, Physiologic, PDZ Domains, Phosphorylation, Protein Binding, Protein Structure, Tertiary, Receptors, Prostaglandin, Signal Transduction
Mol. Biol. Cell
Date: Aug. 01, 2011
PubMed ID: 21653824
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