Hemophilic transdimerization and phosphorylation regulates IGPR-1 function
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Abstract
Dysregulation of endothelial cell barrier function is associated with a wide variety of human diseases ranging from tumor metastasis to inflammation. The barrier function of endothelial cells is maintained by cell adhesion molecules (CAMs). Immunoglobulin containing and proline-rich receptor-1(IGPR-1) was recently identified as a novel CAM involved in angiogenesis. However, the molecular mechanism of IGPR-1 function in endothelial cells remains largely unknown. The overarching goals of this study were: (A) to determine molecular mechanism by which IGPR-1 stimulates biological responses in cells and (B) to investigate regulation of phosphorylation of IGPR-1 at serine 220 (Ser220), and its role in IGPR-1 function. Our data demonstrate that IGPR-1 undergoes cis-dimerization, which leads to homophilic trans-dimerization of IGPR-1, which is required for its adhesive function. Moreover, we demonstrate that phosphorylation of Ser220 is regulated by trans-dimerization of IGPR-1 and that Glycogen Synthase Kinase 3 (GSK-3) is responsible for its phosphorylation as over-expression of kinase active increased and kinase inactive inhibited phosphorylation of Ser220, respectively. Taken together, the results demonstrate that the coordinated dimerization of IGPR-1 and its homophilic interaction regulates its adhesive function and serine phosphorylation. The adhesive function of IGPR-1 contributes to the barrier function of endothelial cells.