Significance: There are a limited number of proteins containing the Phox-Bem1 (PB1) protein interaction domain, and almost all of them play some role in endothelial cell (EC) function, health, and homeostasis. Recent Advances: Most of these proteins have been shown to physically interact through PB1-PB1 binding and, as such, are linked together to form complexes that are responsive to hemodynamic force. These complexes range from redox regulation to inflammation to autophagy and back, and they employ multiple feedback mechanisms that are reliant on PB1 domain proteins. Critical Issues: Pathologic roles for PB1 domain-containing proteins have been demonstrated in multiple diseases, including vascular disease, cancer, liver disease, and myriad other concerns. Findings cited in this review show that dimerization of PB1 proteins exerts novel effects on EC function that may be important in multiple cardiovascular diseases, including atherosclerosis, thrombosis, inflammation, and hypertension. Future Directions: As mechanistic understanding of the component pathways (redox regulation, cell polarity, inflammation, atheroprotection, and autophagy) is continually increasing, the larger picture of how these pathways interact with one another is evolving rapidly. We can now evaluate the PB1 domain proteins as a family in the context of multiple phenotypic readouts in EC function as well as evaluate them as drug targets against disease. Antioxid. Redox Signal. 22, 1243–1256.
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