Proteomics reveals Rictor as a noncanonical TGF-β signaling target during aneurysm progression in Marfan mice

American Journal of Physiology. Heart and Circulatory Physiology
Sarah J ParkerJennifer E Van Eyk

Abstract

The objective of the present study was to 1) analyze the ascending aortic proteome within a mouse model of Marfan syndrome (MFS; Fbn1C1041G/+) at early and late stages of aneurysm and 2) subsequently test a novel hypothesis formulated on the basis of this unbiased proteomic screen that links changes in integrin composition to transforming growth factor (TGF)-β-dependent activation of the rapamycin-independent component of mammalian target of rapamycin (Rictor) signaling pathway. Ingenuity Pathway Analysis of over 1,000 proteins quantified from the in vivo MFS mouse aorta by data-independent acquisition mass spectrometry revealed a predicted upstream regulator, Rictor, that was selectively activated in aged MFS mice. We validated this pattern of Rictor activation in vivo by Western blot analysis for phosphorylation on Thr1135 in a separate cohort of mice and showed in vitro that TGF-β activates Rictor in an integrin-linked kinase-dependent manner in cultured aortic vascular smooth muscle cells. Expression of β3-integrin was upregulated in the aged MFS aorta relative to young MFS mice and wild-type mice. We showed that β3-integrin expression and activation modulated TGF-β-induced Rictor phosphorylation in vitro, and this signalin...Continue Reading

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Citations

Sep 22, 2018·American Journal of Physiology. Heart and Circulatory Physiology·Maria BloksgaardLuis A Martinez-Lemus
Jan 18, 2019·Arteriosclerosis, Thrombosis, and Vascular Biology·Dianna M Milewicz, Francesco Ramirez
Jan 31, 2021·Genes·Tyler J CreamerElena Gallo MacFarlane
Dec 14, 2021·PLoS Computational Biology·Ana C EstradaJay D Humphrey

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Methods Mentioned

BETA
electrophoresis
Affinity Purification
peptide assay

Software Mentioned

DIA
mapDIA
Ingenuity Pathway Analysis ( IPA ) suite
Cytoscape custom network generation
X Analyzer
Hybrid Cell Count
BZ
Ingenuity Pathway
OpenSWATH
MS

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