Cultured endothelial cells display endogenous activation of the canonical Wnt signaling pathway and express multiple ligands, receptors, and secreted modulators of Wnt signaling

Goodwin, Anne M.; Sullivan, Kaitlyn; D'Amore, Patricia A.

doi:10.1002/dvdy.20939

Cited by 100 publications

(103 citation statements)

References 41 publications

(44 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A number of recent studies have observed up-regulation of Wnt/␤-catenin signaling and pathway components upon placing primary cells in culture (63,64). Moreover, Wnts are known to bind the extracellular matrix (65), and heparin has been shown to enhance ␤-catenin signaling activation, presumably by preventing the sequestration of Wnts by matrix components (66,67).…”

Section: Discussionmentioning

confidence: 99%

β-Catenin/T-cell Factor Signaling Is Activated during Lung Injury and Promotes the Survival and Migration of Alveolar Epithelial Cells

Flozak

Lam

Russell

et al. 2010

Journal of Biological Chemistry

112

117

View full text Add to dashboard Cite

The Wnt/␤-catenin signaling cascade activates genes that allow cells to adopt particular identities throughout development. In adult self-renewing tissues like intestine and blood, activation of the Wnt pathway maintains a progenitor phenotype, whereas forced inhibition of this pathway promotes differentiation. In the lung alveolus, type 2 epithelial cells (AT2) have been described as progenitors for the type 1 cell (AT1), but whether AT2 progenitors use the same signaling mechanisms to control differentiation as rapidly renewing tissues is not known. We show that adult AT2 cells do not exhibit constitutive ␤-catenin signaling in vivo, using the AXIN2

show abstract

Section: Discussionmentioning

confidence: 99%

β-Catenin/T-cell Factor Signaling Is Activated during Lung Injury and Promotes the Survival and Migration of Alveolar Epithelial Cells

Flozak

Lam

Russell

et al. 2010

Journal of Biological Chemistry

112

117

View full text Add to dashboard Cite

show abstract

“…Moreover, there is already evidence that circulating Wnt ligands levels may be modified in disease states (28,29). There are many potential sources of circulating Wnt ligands including activated platelets, endothelial cells or possibly other circulating cells (30,31). Further studies will be necessary to understand how the interplay of various Wnt ligands can modulate platelet function but one could hypothesize based on our genetic studies that Wnt agonists acting through Fzd6 may dampen platelet reactivity, akin to other endogenous regulators such as prostacyclin and nitric oxide.…”

Section: Discussionmentioning

confidence: 99%

Canonical Wnt signaling negatively regulates platelet function

Steele

Harper

Macaulay

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Wnts regulate important intracellular signaling events, and dysregulation of the Wnt pathway has been linked to human disease. Here, we uncover numerous Wnt canonical effectors in human platelets where Wnts, their receptors, and downstream signaling components have not been previously described. We demonstrate that the Wnt3a ligand inhibits platelet adhesion, activation, dense granule secretion, and aggregation. Wnt3a also altered platelet shape change and inhibited the activation of the small GTPase RhoA. In addition, we found the Wnt-␤-catenin signaling pathway to be functional in platelets. Finally, disruption of the Wnt Frizzled 6 receptor in the mouse resulted in a hyperactivatory platelet phenotype and a reduced sensitivity to Wnt3a. Taken together our studies reveal a novel functional role for Wnt signaling in regulating anucleate platelet function and may provide a tractable target for future antiplatelet therapy.Wnt-␤-catenin pathway ͉ integrin ␣IIb␤3 ͉ frizzled 6 knockout mice A nucleate platelets are the principle effectors of haemostasis and are found circulating in a nonadhesive, quiescent state. At sites of vascular damage, platelets adhere to various exposed subendothelial matrix proteins and are activated, converting from a resting, discoid shape into larger, flattened structures with extended pseudopodia (1). Such activated platelets secrete and synthesize further agonists, inflammatory mediators, and vasoactive substances and through conformational changes in their major integrin receptor, ␣IIb␤3, aggregate to other platelets via fibrinogen (Fb) to form a haemostatic plug (2). Aberrant platelet activation can cause pathological thrombus formation, leading to thrombosis and ultimately vessel occlusion and tissue ischemia, the processes underlying myocardial infarction and stroke. Understanding the regulation of platelet activity is thus fundamental to comprehending thrombotic disorders and developing therapeutic strategies.The mammalian Wnt gene family is comprised of 19 secreted Wnt glycoproteins, which play essential roles in cell proliferation, cell-fate determination, and cell-fate differentiation during embryonic development and adult homeostasis (3, 4). These Wnt ligands activate a number of different signaling pathways via distinct receptors and downstream effectors to mediate effects on gene transcription and cell adhesion/migration (5, 6). For the Wnt-␤-catenin (␤-cat) signaling pathway (Fig. 1A), traditionally referred to as the ''canonical'' pathway, Wnts bind to a surface receptor complex comprised of a Frizzled (Fzd) receptor and the Lipoprotein Receptor-related Protein 5/6 (LRP5/6) coreceptor (5, 7). The signal is then transduced to the cytoplasmic protein Dishevelled (Dvl) where downstream pathways regulate the stability of ␤-cat (5, 7). In the absence of Wnt, ␤-cat is phosphorylated by a destruction complex containing Casein Kinase 1 (CK1), Glycogen Synthase Kinase 3␤ (GSK3␤), Axin-1, FRAT-1, and Adenomatous Polyposis Coli (APC), which targets ␤-cat for degradation via ubiquitina...

show abstract

“…Furthermore, embryonic aortic endothelial cells from Krit1 null mice are highly proliferative (Whitehead et al, 2004). As -catenin transcriptional activity is implicated in the expression of VEGF (Skurk et al, 2005) and endothelial cell proliferation (Goodwin et al, 2006), we asked whether the expression of VEGFA (Vegfa) or cyclinD1 (Ccnd1) is…”

Section: Krit1 Deficiency Leads To Increased Intestinal Adenoma Formamentioning

confidence: 99%

Rap1 and its effector KRIT1/CCM1 regulate β-catenin signaling

Glading

Ginsberg

2010

Disease Models &Amp; Mechanisms

107

View full text Add to dashboard Cite

SUMMARYKRIT1, also called CCM1, is a member of a multiprotein complex that contains the products of the CCM2 and PDCD10 (also known as CCM3) loci. Heterozygous loss of any of the genes that encode these proteins leads to cerebral cavernous malformations (CCM), which are vascular lesions that are found in around 0.5% of humans. KRIT1 mediates the stabilization of -catenin-containing endothelial cell-cell junctions downstream of the Rap1 GTPase. Here, we report that Rap1 and KRIT1 are negative regulators of canonical -catenin signaling in mice and that hemizygous Krit1 deficiency exacerbates -catenin-driven pathologies. Depletion of endothelial KRIT1 caused -catenin to dissociate from vascular endothelial (VE)-cadherin and to accumulate in the nucleus with consequent increases in -catenin-dependent transcription. Activation of Rap1 inhibited -catenindependent transcription in confluent endothelial cells; this effect required the presence of intact cell-cell junctions and KRIT1. These effects of KRIT1 were not limited to endothelial cells; the KRIT1 protein was expressed widely and its depletion increased -catenin signaling in epithelial cells. Moreover, a reduction in KRIT1 expression also increased -catenin signaling in vivo. Hemizygous deficiency of Krit1 resulted in a ~1.5-fold increase in intestinal polyps in the Apc Min/+ mouse, which was associated with increased -catenin-driven transcription. Thus, KRIT1 regulates -catenin signaling,and Krit1 +/-mice are more susceptible to -catenin-driven intestinal adenomas.

show abstract

Cultured endothelial cells display endogenous activation of the canonical Wnt signaling pathway and express multiple ligands, receptors, and secreted modulators of Wnt signaling

Cited by 100 publications

References 41 publications

β-Catenin/T-cell Factor Signaling Is Activated during Lung Injury and Promotes the Survival and Migration of Alveolar Epithelial Cells

β-Catenin/T-cell Factor Signaling Is Activated during Lung Injury and Promotes the Survival and Migration of Alveolar Epithelial Cells

Canonical Wnt signaling negatively regulates platelet function

Rap1 and its effector KRIT1/CCM1 regulate β-catenin signaling

Contact Info

Product

Resources

About