Wnt5a-mediated non-canonical Wnt signalling regulates human endothelial cell proliferation and migration

Cheng, Ching-wen; Yeh, Ju-Ching; Fan, Tai-Ping; Smith, Stephen K.; Charnock-Jones, D. Stephen

doi:10.1016/j.bbrc.2007.10.166

Cited by 124 publications

(116 citation statements)

References 34 publications

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“…To further investigate whether CD146 can activate non-canonical Wnt signalling JNK alone, the expression levels of Wnt5a and several Wnt receptors were examined by reverse transcriptase-PCR in HEK293T and HUVECs. Our results show that Wnt5a and Wnt receptors were expressed in those cells as reported [21][22][23] . Subsequently, specific siRNAs were employed to knock down the different Wnt receptors in HEK293T cells ( Supplementary Fig.…”

supporting

confidence: 85%

Wnt5a uses CD146 as a receptor to regulate cell motility and convergent extension

Zhang

et al. 2013

Nat Commun

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Dysregulation of Wnt signalling leads to developmental defects and diseases. Non-canonical Wnt signalling via planar cell polarity proteins regulates cell migration and convergent extension; however, the underlying mechanisms are poorly understood. Here we report that Wnt5a uses CD146 as a receptor to regulate cell migration and zebrafish embryonic convergent extension. CD146 binds to Wnt5a with the high affinity required for Wnt5a-induced activation of Dishevelled (Dvl) and c-jun amino-terminal kinase (JNK). The interaction between CD146 and Dvl2 is enhanced on Wnt5a treatment. Mutation of the Dvl2-binding region impairs its ability to activate JNK, promote cell migration and facilitate the formation of cell protrusions. Knockdown of Dvls impairs CD146-induced cell migration. Interestingly, CD146 inhibits canonical Wnt signalling by promoting b-catenin degradation.Our results suggest a model in which CD146 acts as a functional Wnt5a receptor in regulating cell migration and convergent extension, turning off the canonical Wnt signalling branch.

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supporting

confidence: 85%

Wnt5a uses CD146 as a receptor to regulate cell motility and convergent extension

Zhang

et al. 2013

Nat Commun

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“…The Wnt factor Wnt5a was previously described to selectively activate this pathway in various cell types, 25,35 to control multiple cellular functions (cell migration, proliferation, differentiation) and to promote proliferation or survival, particularly in endothelial cells. 36 These pleiotropic effects are mediated through Wnt5a binding to several Fzds, including Fzd-2, Fzd-4, Fzd-5, and Fzd-7. 37 In line with these observations, here we report in hCMEC/D3 cells, which express all these Fzds (Table 1), that Wnt5a induced JNK phosphorylation, a hallmark of activation of the Wnt/Par/aPKC PCP pathway, 38 without activating the canonical Wnt/b-catenin pathway ( Figure 6).…”

Section: Discussionmentioning

confidence: 99%

The Wnt/Planar Cell Polarity Signaling Pathway Contributes to the Integrity of Tight Junctions in Brain Endothelial Cells

Artus

Glacial

Ganeshamoorthy

et al. 2013

J Cereb Blood Flow Metab

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Wnt morphogens released by neural precursor cells were recently reported to control blood-brain barrier (BBB) formation during development. Indeed, in mouse brain endothelial cells, activation of the Wnt/b-catenin signaling pathway, also known as the canonical Wnt pathway, was shown to stabilize endothelial tight junctions (TJs) through transcriptional regulation of the expression of TJ proteins. Because Wnt proteins activate several distinct b-catenin-dependent and independent signaling pathways, this study was designed to assess whether the noncanonical Wnt/Par/aPKC planar cell polarity (PCP) pathway might also control TJ integrity in brain endothelial cells. First we established, in the hCMEC/D3 human brain endothelial cell line, that the Par/aPKC PCP complex colocalizes with TJs and controls apicobasal polarization. Second, using an siRNA approach, we showed that the Par/aPKC PCP complex regulates TJ stability and reassembling after osmotic shock. Finally, we provided evidence that Wnt5a signals in hCMEC/D3 cells through activation of the Par/aPKC PCP complex, independently of the Wnt canonical b-catenin-dependent pathway and significantly contributes to TJ integrity and endothelial apicobasal polarity. In conclusion, this study suggests that the Wnt/Par/aPKC PCP pathway, in addition to the Wnt/b-catenin canonical pathway, is a key regulator of the BBB.

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“…74 Additionally, this pathway is suggested to have a role in inflammatory angiogenesis and vascular remodeling. 75 …”

Section: Canonical Wnt Pathwaymentioning

confidence: 99%

Potential cross-talk between (pro)renin receptors and Wnt/frizzled receptors in cardiovascular and renal disorders

Balakumar

Jagadeesh

2011

Hypertens Res

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The renin-angiotensin system and Wnt/frizzled receptor signaling pathways are important in the development of essential organs, and their aberrant activation results in cardiovascular and renal pathologies. The (pro)renin receptor ((P)RR)-bound (pro)renin is enzymatically active generating angiotensin-II and activating mitogen-activated protein kinases, leading to cell proliferation and to upregulation of profibrotic genes expression, resulting in end-organ damage. The (P)RR does more than bind to (pro)renin, because it is functionally linked to the vacuolar-H + -ATPase (v-H + -ATPase) that regulates pH of cellular and intracellular vesicles, and to Wnt signaling. This signaling pathway is essential for cell survival, embryonic development and has had a role in various disease states as evidenced by mutation or genetic ablation of the (P)RR gene. This suggests two types of functions of (P)RRs, first one as a receptor for (pro)renin and second one as an accessory subunit of the v-H + -ATPase and a cofactor of the Wnt/Fz receptor complex. This review will discuss both of these functions of (P)RRs thereby giving new perspectives as to the roles of (P)RRs in cardiovascular and renal pathologies.

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Wnt5a-mediated non-canonical Wnt signalling regulates human endothelial cell proliferation and migration

Cited by 124 publications

References 34 publications

Wnt5a uses CD146 as a receptor to regulate cell motility and convergent extension

Wnt5a uses CD146 as a receptor to regulate cell motility and convergent extension

The Wnt/Planar Cell Polarity Signaling Pathway Contributes to the Integrity of Tight Junctions in Brain Endothelial Cells

Potential cross-talk between (pro)renin receptors and Wnt/frizzled receptors in cardiovascular and renal disorders

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