The Src Homology and Collagen A (ShcA) Adaptor Protein Is Required for the Spatial Organization of the Costamere/Z-disk Network during Heart Development

Mlih, Mohamed; Host, Lionel; Martin, Sophie; Niederhoffer, Nathalie; Monassier, Laurent; Terrand, Jérôme; Messaddeq, Nadia; Radkë, Michaël; Gotthardt, Michael; Bruban, Véronique; Kober, Frank; Bernard, Monique; Canet-Soulas, Emmanuelle; Abt-Jijon, Francisco; Boucher, Philippe; Matz, Rachel L.

doi:10.1074/jbc.m114.597377

Cited by 6 publications

(15 citation statements)

References 58 publications

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“…We generated Tie2Cre+/ShcA flox/flox mice, in which ShcA is selectively ablated in endothelial cells, by inter-crossing Tie2Cre transgenic mice with floxed ShcA animals 13 (ShcA flox/flox ). To increase atherosclerosis susceptibility, Tie2Cre+/ShcA flox/flox animals were maintained on a LDL receptor-deficient background (LDLR−), fed an atherogenic diet, and are hereafter referred to as endoShcA-.…”

Section: Resultsmentioning

confidence: 99%

“…In particular, it does not indicate in which vascular cell type ShcA deletion would be atheroprotective. We previously reported that the deletion of ShcA in vSMCs did not modify the development of atherosclerotic lesions in mice fed an atherogenic diet 13 . Here, to study the role of ShcA in atherosclerosis and vascular remodeling, we suppressed its expression specifically in endothelial cells using the Cre/lox system.…”

Section: Introductionmentioning

confidence: 94%

“…ShcA is expressed in the cardiovascular system early during embryogenesis and in adults, and controls heart development 3 . In the heart, by binding to integrins or dystrophin, it links the extracellular matrix (ECM) to the cytoskeleton and the contractile apparatus 2 , 13 . In the vascular wall, the role of ShcA is not well defined.…”

Section: Introductionmentioning

confidence: 99%

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Loss of the adaptor protein ShcA in endothelial cells protects against monocyte macrophage adhesion, LDL-oxydation, and atherosclerotic lesion formation

Abou-Jaoude¹,

Badique²,

Mlih³

et al. 2018

Sci Rep

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ShcA is an adaptor protein that binds to the cytoplasmic tail of receptor tyrosine kinases and of the Low Density Lipoprotein-related receptor 1 (LRP1), a trans-membrane receptor that protects against atherosclerosis. Here, we examined the role of endothelial ShcA in atherosclerotic lesion formation. We found that atherosclerosis progression was markedly attenuated in mice deleted for ShcA in endothelial cells, that macrophage content was reduced at the sites of lesions, and that adhesion molecules such as the intercellular adhesion molecule-1 (ICAM-1) were severely reduced. Our data indicate that transcriptional regulation of ShcA by the zinc-finger E-box-binding homeobox 1 (ZEB1) and the Hippo pathway effector YAP, promotes ICAM-1 expression independently of p-NF-κB, the primary driver of adhesion molecules expressions. In addition, ShcA suppresses endothelial Akt and nitric oxide synthase (eNOS) expressions. Thus, through down regulation of eNOS and ZEB1-mediated ICAM-1 up regulation, endothelial ShcA promotes monocyte-macrophage adhesion and atherosclerotic lesion formation. Reducing ShcA expression in endothelial cells may represent an obvious therapeutic approach to prevent atherosclerosis.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

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Loss of the adaptor protein ShcA in endothelial cells protects against monocyte macrophage adhesion, LDL-oxydation, and atherosclerotic lesion formation

Abou-Jaoude¹,

Badique²,

Mlih³

et al. 2018

Sci Rep

Self Cite

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“…C57/B6 mice carrying a ShcA allele into which loxP sites are integrated have been generated by gene targeting in embryonic stem cells. LoxP sites have been introduced upstream of exon 2 and downstream of exon 7 (ShcA flox/flox ) (16). Cre-mediated recombination resulted in deletion of a 2-kb fragment containing the sequence encoding the PTB domain required for binding to phosphorylated receptors and for signaling activity.…”

Section: Methodsmentioning

confidence: 99%

“…We generated TwShcA-mice in which ShcA is selectively ablated in chondrocytes by breeding Twist2 transgenic mice with ShcA flox/flox mice (16). In TwShcA-mice, the three isoforms of ShcA were efficiently reduced in chondrocytes isolated from knee articular cartilage, vertebral and costal cartilage but not in non-cartilaginous tissues like lungs or the spleen (supplemental figure A and B).…”

Section: Specific Deletion Of Shca In Chondrocytes Leads To Dwarfismmentioning

confidence: 99%

ShcA promotes chondrocyte hypertrophic commitment and osteoarthritis in mice through RunX2 nuclear translocation and YAP1 inactivation

Abou-Jaoude

Courtes

Badique

et al. 2020

Preprint

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Chondrocyte hypertrophic differentiation, a key process in endochondral ossification (EO), is also a feature of osteoarthritis leading to articular cartilage destruction. ShcA (Src homology and Collagen A) is an adaptor protein that binds to the cytoplasmic tail of receptor tyrosine kinases. We found that deletion of ShcA in chondrocytes of mice inhibits hypertrophic differentiation, alters the EO process, and leads to dwarfism. ShcA promotes ERK1/2 activation, nuclear translocation of the master transcription factor for chondrocyte hypertrophy, RunX2, while maintaining the Runx2 inhibitor YAP1 in its cytosolic inactive form. This leads to hypertrophic commitment and expression of markers of hypertrophy, such as Collagen X. In addition, ShcA deletion in chondrocytes protects from age-related osteoarthritis development in mice. Our results reveal that ShcA integrates multiple stimuli which affect the intracellular signaling processes leading to the hypertrophic commitment of chondrocytes and osteoarthritis.

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Cardiovascular‐specific PSEN1 deletion leads to abnormalities in calcium homeostasis

Song

Zhao

Yang

et al. 2022

Cell Biology International

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Mutations of PSEN1 have been reported in dilated cardiomyopathy pedigrees. Understanding the effects and mechanisms of PSEN1 in cardiomyocytes might have important implications for treatment of heart diseases. Here, we showed that PSEN1 was downregulated in ischemia‐induced failing hearts. Functionally, cardiovascular specific PSEN1 deletion led to spontaneous death of the mice due to cardiomyopathy. At the age of 11 months, the ratio of the heart weight/body weight was slightly lower in the Sm22a‐PSEN1‐KO mice compared with that of the WT mice. Echocardiography showed that the percentage of ejection fraction and fractional shortening was significantly reduced in the Sm22a‐PSEN1‐KO group compared with the percent of these measures in the WT group, indicating that PSEN1‐KO resulted in heart failure. The abnormally regulated genes resulted from PSEN1‐KO were detected to be enriched in muscle development and dilated cardiomyopathy. Among them, several genes encode Ca2+ ion channels, promoting us to investigate the effects of PSEN1 KO on regulation of Ca2+ in isolated adult cardiomyocytes. Consistently, in isolated adult cardiomyocytes, PSEN1‐KO increased the concentration of cytosolic Ca2+ and reduced Ca2+ concentration inside the sarcoplasmic reticulum (SR) lumen at the resting stage. Additionally, SR Ca2+ was decreased in the failing hearts of WT mice, but with the lowest levels observed in the failing hearts of PSEN1 knockout mice. These results indicate that the process of Ca2+ release from SR into cytoplasm was affected by PSEN1 KO. Therefore, the abnormalities in Ca2+ homeostasis resulted from downregulation of PSEN1 in failing hearts might contribute to aging‐related cardiomyopathy, which might had important implications for the treatment of aging‐related heart diseases.

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The Src Homology and Collagen A (ShcA) Adaptor Protein Is Required for the Spatial Organization of the Costamere/Z-disk Network during Heart Development

Cited by 6 publications

References 58 publications

Loss of the adaptor protein ShcA in endothelial cells protects against monocyte macrophage adhesion, LDL-oxydation, and atherosclerotic lesion formation

Loss of the adaptor protein ShcA in endothelial cells protects against monocyte macrophage adhesion, LDL-oxydation, and atherosclerotic lesion formation

ShcA promotes chondrocyte hypertrophic commitment and osteoarthritis in mice through RunX2 nuclear translocation and YAP1 inactivation

Cardiovascular‐specific PSEN1 deletion leads to abnormalities in calcium homeostasis

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