Targeting Wnt Pathways in Disease

Zimmerman, Zachary; Moon, Randall T.; Chien, Andy J.

doi:10.1101/cshperspect.a008086

Cited by 98 publications

(82 citation statements)

References 207 publications

(182 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Nuclear accumulation of β-catenin in response to Wnt signaling drives Tcf/Lef regulation of Wnt-responsive gene expression (Clevers and Nusse, 2012). It is important to note that Lef1-deficient mice have morphogenetic defects in several organs that require epithelial-mesenchymal interactions (van Genderen et al, 1994), and Wnt/β-catenin signaling has been widely proven to be essential for organ growth during development (Clevers and Nusse, 2012;Gessert and Kühl, 2010;Wang et al, 2012;Zimmerman et al, 2012). Based on this, we postulate that aberrant Wnt/β-catenin signaling is a major contributor to the proliferative defects in Tbx20 CKO cushions and valves.…”

Section: Research Articlementioning

confidence: 99%

Tbx20 acts upstream of Wnt signaling to regulate endocardial cushion formation and valve remodeling during mouse cardiogenesis

Cai

Zhang

et al. 2013

Development

View full text Add to dashboard Cite

SUMMARYCardiac valves are essential to direct forward blood flow through the cardiac chambers efficiently. Congenital valvular defects are prevalent among newborns and can cause an immediate threat to survival as well as long-term morbidity. Valve leaflet formation is a rigorously programmed process consisting of endocardial epithelial-mesenchymal transformation (EMT), mesenchymal cell proliferation, valve elongation and remodeling. Currently, little is known about the coordination of the diverse signals that regulate endocardial cushion development and valve elongation. Here, we report that the T-box transcription factor Tbx20 is expressed in the developing endocardial cushions and valves throughout heart development. Ablation of Tbx20 in endocardial cells causes severe valve elongation defects and impaired cardiac function in mice. Our study reveals that endocardial Tbx20 is crucial for valve endocardial cell proliferation and extracellular matrix development, but is not required for initiation of EMT. Elimination of Tbx20 also causes aberrant Wnt/β-catenin signaling in the endocardial cushions. In addition, Tbx20 regulates Lef1, a key transcriptional mediator for Wnt/β-catenin signaling, in this developmental process. Our study suggests a model in which Tbx20 regulates the Wnt pathway to direct endocardial cushion maturation and valve elongation, and provides new insights into the etiology of valve defects in humans.

show abstract

Section: Research Articlementioning

confidence: 99%

Tbx20 acts upstream of Wnt signaling to regulate endocardial cushion formation and valve remodeling during mouse cardiogenesis

Cai

Zhang

et al. 2013

Development

View full text Add to dashboard Cite

show abstract

“…57 Only 20-30% of HER2-positive breast cancer patients respond to trastuzumab monotherapy. 58,59 If WLS is a key component of a pathway responsible for trastuzumab resistance that is expressed across cancer subtypes, then WLS could be targeted therapeutically alone, or in conjunction with trastuzimab, to help overcome resistance.…”

Section: Wls and Her2 In Gastric Ovarian And Breast Cancersmentioning

confidence: 99%

Analysis of wntless (WLS) expression in gastric, ovarian, and breast cancers reveals a strong association with HER2 overexpression

Stewart¹,

James

McCluggage

et al. 2015

Modern Pathology

View full text Add to dashboard Cite

The oncogenic role of WNT is well characterized. Wntless (WLS) (also known as GPR177, or Evi), a key modulator of WNT protein secretion, was recently found to be highly overexpressed in malignant astrocytomas. We hypothesized that this molecule may be aberrantly expressed in other cancers known to possess aberrant WNT signaling such as ovarian, gastric, and breast cancers. Immunohistochemical analysis using a TMA platform revealed WLS overexpression in a subset of ovarian, gastric, and breast tumors; this overexpression was associated with poorer clinical outcomes in gastric cancer (P ¼ 0.025). In addition, a strong correlation was observed between WLS expression and human epidermal growth factor receptor 2 (HER2) overexpression. Indeed, 100% of HER2-positive intestinal gastric carcinomas, 100% of HER2-positive serous ovarian carcinomas, and 64% of HER2-positive breast carcinomas coexpressed WLS protein. Although HER2 protein expression or gene amplification is an established predictive biomarker for trastuzumab response in breast and gastric cancers, a significant proportion of HER2-positive tumors display resistance to trastuzumab, which may be in part explainable by a possible mechanistic link between WLS and HER2. Modern Pathology (2015) 28, 428-436; doi:10.1038/modpathol.2014 published online 26 September 2014 The molecular mechanisms controlling the maturation and secretion of WNT proteins in the cells responsible for their production are attracting considerable attention. Wntless (WLS) (also known as GPR177 and Evi) was recently discovered as a key modulator of WNT protein secretion. [1][2][3] This multipass transmembrane protein localizes to compartments of the secretory pathway including the Golgi apparatus, endosomes, and plasma membrane. WLS acts as a WNT cargo receptor, shuttling palmitoylated Wnts from the endoplasmic reticulum to the plasma membrane, and it is required for exocytosis of WNT proteins from the WNT-producing cells. 4 In contrast to most other components of the WNT signaling pathway, only a single WLS gene exists in vertebrate genomes. WLS appears to be required for the secretion of all WNT proteins in both the canonical and noncanonical WNT pathways. 5 Augustin et al 6 recently demonstrated that WLS is highly overexpressed in malignant astrocytomas, indicating that the aberrant release of canonical and noncanonical WNT is a potential driver of glioma tumorigenesis required for proliferation, survival, and migration of glioma cells. Their work raises the question of whether WLS has a similar role in other cancers known to have aberrant activation of WNT signaling, including ovarian, gastric, and breast cancers. [7][8][9][10][11][12][13][14][15]

show abstract

“…Short episodes of Wnt exposure are all that is needed for embryonic development and likely this is all that would be needed in tissue engineering as well (Zimmerman et al 2012). Wnt has a broad range of targets and responses, however, making it undesirable for clinical application in engineering human tissue, but R-spondins have potential to more specifically enhance engineered intestinal growth (Belchior et al 2014).…”

Section: Tissue Engineering Functional Gastrointestinal Regionsmentioning

confidence: 99%

Tissue Engineering Functional Gastrointestinal Regions: The Importance of Stem and Progenitor Cells

Trecartin

Grikscheit

2017

Cold Spring Harb Perspect Med

View full text Add to dashboard Cite

Targeting Wnt Pathways in Disease

Cited by 98 publications

References 207 publications

Tbx20 acts upstream of Wnt signaling to regulate endocardial cushion formation and valve remodeling during mouse cardiogenesis

Tbx20 acts upstream of Wnt signaling to regulate endocardial cushion formation and valve remodeling during mouse cardiogenesis

Analysis of wntless (WLS) expression in gastric, ovarian, and breast cancers reveals a strong association with HER2 overexpression

Tissue Engineering Functional Gastrointestinal Regions: The Importance of Stem and Progenitor Cells

Contact Info

Product

Resources

About