title: Interaction of the human prostacyclin receptor and the NHERF4 family member intestinal and kidney enriched PDZ protein (IKEPP).
abstract: Prostacyclin and its I prostanoid receptor, the IP, play central roles in hemostasis and in re-endothelialization in response to vascular injury. Herein, intestinal and kidney enriched PDZ protein (IKEPP) was identified as an interactant of the human (h) IP mediated through binding of PDZ domain 1 (PDZ(D1)) and, to a lesser extent, PDZ(D2) of IKEPP to a carboxyl-terminal Class I 'PDZ ligand' within the hIP. While the interaction is constitutive, agonist-activation of the hIP leads to cAMP-dependent protein kinase (PK) A and PKC-phosphorylation of IKEPP, coinciding with its increased interaction with the hIP. Ectopic expression of IKEPP increases functional expression of the hIP, enhancing its ligand binding and agonist-induced cAMP generation. Originally thought to be restricted to renal and gastrointestinal tissues, herein, IKEPP was also found to be expressed in vascular endothelial cells where it co-localizes and complexes with the hIP. Furthermore, siRNA-disruption of IKEPP expression impaired hIP-induced endothelial cell migration and in vitro angiogenesis, revealing the functional importance of the IKEPP:IP interaction within the vascular endothelium. Identification of IKEPP as a functional interactant of the IP reveals novel mechanistic insights into the role of these proteins within the vasculature and, potentially, in other systems where they are co-expressed.
authors.affiliation: School of Biomolecular and Biomedical Sciences, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Reid
authors.forename: Elizebeth C
authors.initials: EC
authors.lastname: Turner
authors.forename: Eamon P
authors.initials: EP
authors.lastname: Mulvaney
authors.forename: Paula B
authors.initials: PB
authors.lastname: Hyland
authors.forename: Caitriona
authors.initials: C
authors.lastname: McLean
authors.forename: B Therese
authors.initials: BT
authors.lastname: Kinsella
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D015815:Cell Adhesion Molecules; D002465:Cell Movement; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology; D008024:Ligands; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D017434:Protein Structure, Tertiary; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D017923:Sodium-Hydrogen Exchangers / Q000737:chemistry / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D008024:Ligands; D009363:Neoplasm Proteins; C423943:PDZD2 protein, human; C113936:PTGIR protein, human; D010750:Phosphoproteins; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D017923:Sodium-Hydrogen Exchangers; C093376:sodium-hydrogen exchanger regulatory factor; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C