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.

No abstract

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

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.

No abstract