Integrin alpha 5 beta 1 regulates PP2A complex assembly through PDE4D in atherosclerosis

• Authors: Sanguk Yun, Yale University; Rui Hu, Yale University; Melanie E. Schwaemmle, Yale University; Alexander N. Scherer, Yale University; Zhenwu Zhuang, Yale University; Anthony J. Koleske, Yale University; David Pallas, Emory University; Martin A. Schwartz, Yale University
• Journal Title: JOURNAL OF CLINICAL INVESTIGATION
• Volume: Volume 129, Number 11
• Publisher: AMER SOC CLINICAL INVESTIGATION INC | 2019-11-01, Pages 4863-4874
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1172/JCI127692
• Subjects: Biology, Genetics
• Keywords: Science & Technology; Life Sciences & Biomedicine; Medicine, Research & Experimental; Research & Experimental Medicine; KAPPA-B ACTIVATION; REDUCES ATHEROSCLEROSIS; FIBRONECTIN DEPOSITION; IN-VIVO; PROTEIN; ANGIOGENESIS; EXPRESSION; YAP/TAZ; GROWTH; FLOW

Abstract

Fibronectin in the vascular wall promotes inflammatory activation of the endothelium during vascular remodeling and atherosclerosis. These effects are mediated in part by fibronectin binding to integrin α5, which recruits and activates phosphodiesterase 4D5 (PDE4D5) by inducing its dephosphorylation on an inhibitory site, S651. Active PDE then hydrolyzes antiinflammatory cAMP to facilitate inflammatory signaling. To test this model in vivo, we mutated the integrin binding site of PDE4D5 in mice. This mutation reduced endothelial inflammatory activation in atherosclerosis-prone regions of arteries and, in a hyperlipidemia model, reduced atherosclerotic plaque size while increasing markers of plaque stability. We then investigated the mechanism of PDE4D5 activation. Proteomics identified the PP2A regulatory subunit B55α as the factor recruiting PP2A to PDE4D5. The B55α-PP2A complex localized to adhesions and directly dephosphorylated PDE4D5. This interaction also, unexpectedly, stabilized the PP2A-B55α complex. The integrin-regulated, proatherosclerotic transcription factor Yap was also dephosphorylated and activated through this pathway. PDE4D5 therefore mediated matrix-specific regulation of endothelial cell phenotype via an unconventional adapter role, assembling and anchoring a multifunctional PP2A complex that has other targets. We believe these results may have widespread consequences for the control of cell function by integrins.