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Integrin ?5?1 regulates PP2A complex assembly through PDE4D in atherosclerosis.


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 ?5, which recruits and activates phosphodiesterase 4D5 (PDE4D5) by inducing its dephosphorylation on an inhibitory site Ser651. Active PDE then hydrolyzes anti-inflammatory cAMP to facilitate inflammatory signaling. To test this model in vivo, we mutated the integrin binding site in PDE4D5 in mice. This mutation reduced endothelial inflammatory activation in athero-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 B55? as the factor recruiting PP2A to PDE4D5. The B55?-PP2A complex localized to adhesions and directly dephosphorylated PDE4D5. This interaction also unexpectedly stabilized the PP2A-B55? complex. The integrin-regulated, pro-atherosclerotic transcription factor Yap is also dephosphorylated and activated through this pathway. PDE4D5 therefore mediates matrix-specific regulation of EC phenotype via an unconventional adapter role, assembling and anchoring a multifunctional PP2A complex with other targets. These results are likely to have widespread consequences for control of cell function by integrins.

SUBMITTER: Yun S 

PROVIDER: S-EPMC6819111 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Integrin α5β1 regulates PP2A complex assembly through PDE4D in atherosclerosis.

Yun Sanguk S   Hu Rui R   Schwaemmle Melanie E ME   Scherer Alexander N AN   Zhuang Zhenwu Z   Koleske Anthony J AJ   Pallas David C DC   Schwartz Martin A MA  

The Journal of clinical investigation 20190813 11


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 Ser651. Active PDE then hydrolyzes anti-inflammatory cAMP to facilitate inflammatory signaling. To test this model in vivo, we mutated the integrin binding site in PDE4D5 in mic  ...[more]

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