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Interaction of the human Prostacyclin receptor with the PDZ adapter protein PDZK1: Role in Endothelial Cell Migration and Angiogenesis
Author(s) -
Kinsella B Therese,
Mulvaney Eamon P,
Turner Elizebeth C,
Reid Helen M
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.837.3
Subject(s) - angiogenesis , pdz domain , microbiology and biotechnology , prostacyclin , small interfering rna , chemistry , endothelial stem cell , phosphorylation , biology , cancer research , transfection , biochemistry , in vitro , gene
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. The interaction is constitutive, but 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 cAMP generation. Consistent with a role in re‐endothelialization and angiogenesis, cicaprost activation of the hIP increased endothelial cell migration and tube formation/in vitro angiogenesis, effects abrogated by the specific IP antagonist RO1138452. Furthermore, similar to HDL/SR‐B1, small interfering RNA ( si RNA)‐targeted disruption of PDZK1 abolished cicaprost‐mediated endothelial responses but did not affect VEGF responses. The identification of PDZK1 as a functional interactant of the hIP sheds significant mechanistic insights into the protective roles of these key players within the vascular endothelium. Funded by SFI.