| First Author | Parker SJ | Year | 2018 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 315 |
| Issue | 5 | Pages | H1112-H1126 |
| PubMed ID | 30004239 | Mgi Jnum | J:266128 |
| Mgi Id | MGI:6202511 | Doi | 10.1152/ajpheart.00089.2018 |
| Citation | Parker SJ, et al. (2018) Proteomics reveals Rictor as a noncanonical TGF-beta signaling target during aneurysm progression in Marfan mice. Am J Physiol Heart Circ Physiol 315(5):H1112-H1126 |
| abstractText | The objective of the present study was to 1) analyze the ascending aortic proteome within a mouse model of Marfan syndrome (MFS; Fbn1(C1041G/+)) 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)-beta-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 Thr(1135) in a separate cohort of mice and showed in vitro that TGF-beta activates Rictor in an integrin-linked kinase-dependent manner in cultured aortic vascular smooth muscle cells. Expression of beta3-integrin was upregulated in the aged MFS aorta relative to young MFS mice and wild-type mice. We showed that beta3-integrin expression and activation modulated TGF-beta-induced Rictor phosphorylation in vitro, and this signaling effect was associated with an altered vascular smooth muscle cell proliferative-migratory and metabolic in vitro phenotype that parallels the in vivo aneurysm phenotype in MFS. These results reveal that Rictor is a novel, context-dependent, noncanonical TGF-beta signaling effector with potential pathogenic implications in aortic aneurysm. NEW & NOTEWORTHY We present the most comprehensive quantitative analysis of the ascending aortic aneurysm proteome in Marfan syndrome to date resulting in novel and potentially wide-reaching findings that expression and signaling by beta3-integrin constitute a modulator of transforming growth factor-beta-induced rapamycin-independent component of mammalian target of rapamycin (Rictor) signaling and physiology in aortic vascular smooth muscle cells. |
