Shc coordinates signals from intercellular junctions and integrins to regulate flow-induced inflammation

Sweet, Daniel T.; Irani-Tehrani, Mohamad; Maeda, Nobuyo; Tzima, Ellie

doi:10.1083/jcb.200709176

Cited by 55 publications

(75 citation statements)

References 51 publications

(72 reference statements)

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“…44 Hemodynamic forces are emerging as an important regulator of angiogenesis in some vascular beds such as the aortic arch 45,46 and yolk sac 47 in both the mouse and fish. Flow also promotes hematopoietic cell development 48,49 in vivo and atheroprotective laminar flow inhibits HUVEC tubule formation and migration in vitro.…”

Section: Discussionmentioning

confidence: 99%

The adaptor protein Shc integrates growth factor and ECM signaling during postnatal angiogenesis

Sweet

Chen

Wiley³

et al. 2012

Blood

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IntroductionAngiogenesis, the sprouting and growth of new blood vessels from preexisting vasculature, is critical for wound healing and in diseases such as rheumatoid arthritis, diabetes, and cancer. 1 Angiogenesis is a highly coordinated tissue-remodeling process activated by proangiogenic growth factors such as VEGF, the expression of which is up-regulated in hypoxic or cancer cells. VEGF receptors expressed on the endothelial cell (EC) surface become activated when bound to the VEGF ligand, initiating signaling cascades that lead to EC proliferation, migration, survival, and tube formation. 2 Basement membrane deposition and mechanical cues from the ECM transmitted via integrins also participate to coordinate vessel sprouting and remodeling in conjunction with the VEGF signaling pathway. 3 Given their transmembrane structure, ability to form associations with adaptor molecules, and ability to bind to extracellular ligands, VEGF receptors and integrins are well positioned to serve as functional hubs during the angiogenic process. 4 Adaptor proteins, which have no catalytic activity but instead promote protein-protein interactions, are important regulators of signaling pathways downstream of activated cell-surface receptors. 5 The prototypical adaptor protein Shc is an evolutionarily conserved, ubiquitously expressed protein that was originally described as an oncogene because of its participation in the activation of Ras and MAPKs downstream of a multitude of receptors for various growth factors, cytokines, and hormones. 6,7 Shc is expressed as 3 isoforms of 46, 52, and 66 kDa, all of which are products of the same gene, Shc1. 8,9 Global knockout of Shc1 in mice causes embryonic lethality at embryonic day 11.5. 10 These embryos exhibit severe defects in the cardiovascular system, including defective heart development and vessel remodeling. More detailed gene-targeting work has shown that the expression of the PTB domain of Shc specifically in cardiomyocytes is critical for midgestational heart development and embryonic life. 11 Conditional knockout strategies have shown that Shc is also important for the proper development/function of other organs such as skeletal muscle, 11 brain, 12 cardiomyocytes, 13 and thymocytes, 14 because tissue-specific deletion of Shc resulted in living but underdeveloped mice. To address the role of Shc in angiogenesis in vivo, we studied loss of Shc function using morpholino (MO) antisense technology in zebrafish. In addition, we used the Tie2-Cre transgene to generate mice null for Shc in ECs and some hematopoietic cells. 15 Surprisingly, these mice survived through development, enabling us to investigate the role of Shc in postnatal angiogenesis. We show herein that Shc is required for proper angiogenesis in vivo in both the zebrafish and mouse. Mechanistically, Shc is required for transmitting signals downstream of 2 major angiogenic signaling hubs, VEGFR-2 and integrins. Methods Zebrafish MO injectionTwo splice-blocking MOs targeting the zebrafish ortholog of Shc1 (accession nu...

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Section: Discussionmentioning

confidence: 99%

The adaptor protein Shc integrates growth factor and ECM signaling during postnatal angiogenesis

Sweet

Chen

Wiley³

et al. 2012

Blood

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“…In this model, mechanical forces exerted on endothelial cells by shear stress are directly transduced through PECAM1, VE-cadherin serves as an essential adaptor between PECAM1 and VEGFR, and VEGFR, in turn, activates PI3K and results in PI3K-mediated activation of integrins to regulate cell alignment in the direction of the shear stress. This crosstalk between VE-cadherin and integrins is coordinated in part by the Shc adaptor protein (Liu et al, 2008).…”

Section: Regulation Of Mechanosignaling and Forces By Crosstalk Betwementioning

confidence: 99%

The mechanical regulation of integrin–cadherin crosstalk organizes cells, signaling and forces

Mui

Chen

Assoian

2016

Journal of Cell Science

270

224

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Cadherins and integrins are intrinsically linked through the actin cytoskeleton and share common signaling molecules. Although mechanosensing by the integrin-actin axis has long been appreciated, a growing body of literature now demonstrates that cadherins also transduce and respond to mechanical forces. Mounting evidence shows that mechanically driven crosstalk between integrins and cadherins regulates the spatial distribution of these receptors, their signaling intermediates, the actin cytoskeleton and intracellular forces. This interplay between integrins and cadherins can control fibronectin matrix assembly and signaling, and a fine balance between traction forces at focal adhesions and intercellular tension at adherens junctions is crucial for directional collective cell migration. In this Commentary, we discuss two central ideas: (1) how the dynamic interplay between integrins and cadherins regulates the spatial organization of intracellular signals and the extracellular matrix, and (2) the emerging consensus that intracellular force is a central mechanism that dictates cell behavior, guides tissue development and ultimately drives physiology.

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“…Onset of flow abruptly changes the angle between cells, transmitting tension to the proteins that form the adherens junction (1188). Signals are then generated which require platelet and endothelial cell adhesion molecule 1 (PECAM-1), VEcadherin, and vascular endothelial growth factor receptor 2 (VEGFR2, also called Flk-1) (1064,1828). PECAM-1 appears to act as the true mechanical transducer and generates an array of signals.…”

Section: Endothelial Mechanotransduction Through the Adherens Junctiomentioning

confidence: 99%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

387

344

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At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

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Shc coordinates signals from intercellular junctions and integrins to regulate flow-induced inflammation

Cited by 55 publications

References 51 publications

The adaptor protein Shc integrates growth factor and ECM signaling during postnatal angiogenesis

The adaptor protein Shc integrates growth factor and ECM signaling during postnatal angiogenesis

The mechanical regulation of integrin–cadherin crosstalk organizes cells, signaling and forces

Molecular Biology of Atherosclerosis

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