scholarly journals The Crosstalk between FAK and Wnt Signaling Pathways in Cancer and Its Therapeutic Implication

2020 ◽  
Vol 21 (23) ◽  
pp. 9107
Author(s):  
Janine Wörthmüller ◽  
Curzio Rüegg
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Functional Interaction ◽  
Mucosal Regeneration ◽  
Pancreatic Cancers ◽  
Dependent Relationship ◽  
Context Specific ◽  
Wnt Inhibitors

Focal adhesion kinase (FAK) and Wnt signaling pathways are important contributors to tumorigenesis in several cancers. While most results come from studies investigating these pathways individually, there is increasing evidence of a functional crosstalk between both signaling pathways during development and tumor progression. A number of FAK–Wnt interactions are described, suggesting an intricate, context-specific, and cell type-dependent relationship. During development for instance, FAK acts mainly upstream of Wnt signaling; and although in intestinal homeostasis and mucosal regeneration Wnt seems to function upstream of FAK signaling, FAK activates the Wnt/β-catenin signaling pathway during APC-driven intestinal tumorigenesis. In breast, lung, and pancreatic cancers, FAK is reported to modulate the Wnt signaling pathway, while in prostate cancer, FAK is downstream of Wnt. In malignant mesothelioma, FAK and Wnt show an antagonistic relationship: Inhibiting FAK signaling activates the Wnt pathway and vice versa. As the identification of effective Wnt inhibitors to translate in the clinical setting remains an outstanding challenge, further understanding of the functional interaction between Wnt and FAK could reveal new therapeutic opportunities and approaches greatly needed in clinical oncology. In this review, we summarize some of the most relevant interactions between FAK and Wnt in different cancers, address the current landscape of Wnt- and FAK-targeted therapies in different clinical trials, and discuss the rationale for targeting the FAK–Wnt crosstalk, along with the possible translational implications.

scholarly journals Genetic Polymorphism in Extracellular Regulators of Wnt Signaling Pathway

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Garima Sharma ◽  
Ashish Ranjan Sharma ◽  
Eun-Min Seo ◽  
Ju-Suk Nam
Keyword(s):  
Genetic Polymorphism ◽  
Wnt Signaling ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
The Other ◽  
Present Review ◽  
Receptor Complex ◽  
Related Proteins ◽  
Related Association

The Wnt signaling pathway is mediated by a family of secreted glycoproteins through canonical and noncanonical mechanism. The signaling pathways are regulated by various modulators, which are classified into two classes on the basis of their interaction with either Wnt or its receptors. Secreted frizzled-related proteins (sFRPs) are the member of class that binds to Wnt protein and antagonizes Wnt signaling pathway. The other class consists of Dickkopf (DKK) proteins family that binds to Wnt receptor complex. The present review discusses the disease related association of various polymorphisms in Wnt signaling modulators. Furthermore, this review also highlights that some of the sFRPs and DKKs are unable to act as an antagonist for Wnt signaling pathway and thus their function needs to be explored more extensively.

sFRP1 Expression Regulates Wnt signaling in Chronic Myeloid Leukemia K562 Cells

2021 ◽  
Vol 21 ◽  
Author(s):  
Melek Pehlivan ◽  
Ceyda Caliskan ◽  
Zeynep Yuce ◽  
Hakki O. Sercan
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Myeloid Leukemia ◽  
Wnt Signaling Pathway ◽  
K562 Cells ◽  
New Agents ◽  
Cell Fate Decisions ◽  
Sfrp1 Expression ◽  
Wnt Inhibitors

Background: Wnt signaling cascades play important roles in cell fate decisions and their deregulation has been documented in many diseases, including malignant tumors and leukemia. One mechanism of aberrant Wnt signaling is the silencing of Wnt inhibitors through epigenetic mechanisms. The sFRPs are one of the most studied Wnt inhibitors; and the sFRP1 loss is known in many hematological malignancies. Therefore, we aimed to compare the expression of Wnt related genes in the presence and absence of sFRP1 in chronic myeloid leukemia (CML) cell line. Objective: It is important to understand how sFRP1 and sFRP1 perform on CML to design new agents and strategies for resistant and advanced forms of CML. Materials and Methods: We used K562 cells, which normally do not express sFRP1 and its sFRP1 expressing subclone K562s. Total RNA was isolated from K562 and K562s cell lines end converted cDNA. PCR Array experiments performed using Human Wnt Signaling Pathway Plus RT2 Profiler™ kit. Wnt signaling pathway activation was studied by western blot for downstream signaling targets. Results: The WNT3, LRP6, PRICKLE1 and BTRC expressions were significantly decreased in the presence of sFRP1; while WNT5B increased. The sFRP1 expression inhibited stabilization of total β-catenin protein and downstream effector phosphorylation of noncanonical Wnt/PCP signaling; whereas Ca2+/PKC signaling remained active. Conclusion: The results suggest that sFRP1 could be a promising therapeutic anticancer agent. Defining these pathway interactions is crucial to design new agents resistant and advanced forms of CML.

scholarly journals Modulation of Calretinin Expression in Human Mesothelioma Cells Reveals the Implication of the FAK and Wnt Signaling Pathways in Conferring Chemoresistance towards Cisplatin

2019 ◽  
Vol 20 (21) ◽  
pp. 5391 ◽  
Author(s):  
Wörthmüller ◽  
Salicio ◽  
Oberson ◽  
Blum ◽  
Schwaller
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Expression System ◽  
Single Agent ◽  
Wnt Signaling Pathway ◽  
Tumor Formation ◽  
Mesenchymal Transition

Malignant mesothelioma (MM) is an aggressive asbestos-linked neoplasm, characterized by dysregulation of signaling pathways. Due to intrinsic or acquired chemoresistance, MM treatment options remain limited. Calretinin is a Ca2+-binding protein expressed during MM tumorigenesis that activates the FAK signaling pathway, promoting invasion and epithelial-to-mesenchymal transition. Constitutive calretinin downregulation decreases MM cells’ growth and survival, and impairs tumor formation in vivo. In order to evaluate early molecular events occurring during calretinin downregulation, we generated a tightly controlled IPTG-inducible expression system to modulate calretinin levels in vitro. Calretinin downregulation significantly reduced viability and proliferation of MM cells, attenuated FAK signaling and reduced the invasive phenotype of surviving cells. Importantly, surviving cells showed a higher resistance to cisplatin due to increased Wnt signaling. This resistance was abrogated by the Wnt signaling pathway inhibitor 3289-8625. In various MM cell lines and regardless of calretinin expression levels, blocking of FAK signaling activated the Wnt signaling pathway and vice versa. Thus, blocking both pathways had the strongest impact on MM cell proliferation and survival. Chemoresistance mechanisms in MM cells have resulted in a failure of single-agent therapies. Targeting of multiple components of key signaling pathways, including Wnt signaling, might be the future method-of-choice to treat MM.

scholarly journals Autophagy Is Required for Hepatic Differentiation of Hepatic Progenitor Cells via Wnt Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Jianxing Zeng ◽  
Yingying Jing ◽  
Qionglan Wu ◽  
Jinhua Zeng ◽  
Lixin Wei ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathways ◽  
Progenitor Cells ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Wnt Signaling Pathway ◽  
Hepatic Progenitor Cells ◽  
Hepatic Differentiation ◽  
Development And Differentiation ◽  
Progenitor Cell Line

The molecular mechanisms regulating differentiation of hepatic progenitor cells (HPCs), which play pivotal roles in liver regeneration and development, remain obscure. Autophagy and Wnt signaling pathways regulate the development and differentiation of stem cells in various organs. However, the roles of autophagy and Wnt signaling pathways in hepatic differentiation of HPCs are not well understood. Here, we describe the effects of autophagy and Wnt signaling pathways during hepatic differentiation of HPCs. We used a well-established rat hepatic progenitor cell line called WB-F344, which was treated with differentiation medium to promote differentiation of WB-F344 cells along the hepatic phenotype. Firstly, autophagy was highly activated in HPCs and gradually decreased during hepatic differentiation of HPCs. Induction of autophagy by rapamycin or starvation suppressed hepatic differentiation of HPCs. Secondly, Wnt3a signaling pathway was downregulated, and Wnt5a signaling pathway was upregulated in hepatic differentiation of HPCs. At last, Wnt3a signaling pathway was enhanced, and Wnt5a signaling pathway was inhibited by activation of autophagy during hepatic differentiation of HPCs. In summary, these results demonstrate that autophagy regulates hepatic differentiation of hepatic progenitor cells through Wnt signaling pathway.

Functional interaction of TCF4 with ATF5 to regulate the Wnt signaling pathway

2003 ◽  
Vol 48 (7) ◽  
pp. 668-672
Author(s):  
Xiongjun Ye ◽  
Zhiwen Zhang ◽  
Xinjun Zhang ◽  
Guiting Lin ◽  
Shiqin Xiong ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Functional Interaction

Epigenetic regulation of Wnt-signaling pathway in acute lymphoblastic leukemia

Blood ◽  
2006 ◽  
Vol 109 (8) ◽  
pp. 3462-3469 ◽  
Author(s):  
José Román-Gómez ◽  
Lucia Cordeu ◽  
Xabier Agirre ◽  
Antonio Jiménez-Velasco ◽  
Edurne San José-Eneriz ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Wnt Signaling Pathway ◽  
Disease Free Survival ◽  
Wnt Inhibitor ◽  
Wnt Inhibitors

Abstract Activation of the Wnt/β-catenin signaling pathway is a hallmark of a number of solid tumors. We analyzed the regulation of the Wnt/β-catenin pathway in acute lymphoblastic leukemia (ALL) and its role in the pathogenesis of the disease. We found that expression of the Wnt inhibitors sFRP1, sFRP2, sFRP4, sFRP5, WIF1, Dkk3, and Hdpr1 was down-regulated due to abnormal promoter methylation in ALL cell lines and samples from patients with ALL. Methylation of Wnt inhibitors was associated with activation of the Wnt-signaling pathway as demonstrated by the up-regulation of the Wnt target genes WNT16, FZ3, TCF1, LEF1, and cyclin D1 in cell lines and samples and the nuclear localization of β-catenin in cell lines. Treatment of ALL cells with the Wnt inhibitor quercetin or with the demethylating agent 5-aza-2′-deoxycytidine induced an inactivation of the Wnt pathway and induced apoptosis of ALL cells. Finally, in a group of 261 patients with newly diagnosed ALL, abnormal methylation of Wnt inhibitors was associated with decreased 10-year disease-free survival (25% versus 66% respectively, P < .001) and overall survival (28% versus 61% respectively, P = .001). Our results indicate a role of abnormal Wnt signaling in ALL and establish a group of patients with a significantly worse prognosis (methylated group).

scholarly journals Novel newt regeneration genes regulate Wingless signaling to restore patterning in Drosophila eye

2021 ◽  
Author(s):  
Abijeet Singh Mehta ◽  
Prajakta Deshpande ◽  
Anuradha Venkatakrishnan Chimata ◽  
Panagiotis A. Tsonis ◽  
Amit Singh
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Ectopic Expression ◽  
Wnt Signaling Pathway ◽  
Protein S ◽  
Photoreceptor Cells ◽  
Body Parts ◽  
Regeneration Potential ◽  
Regeneration Capability

AbstractA fundamental process of regeneration, which varies among animals, recruits conserved signaling pathways to restore missing parts. Only a few animals like newts can repeatedly regenerate lost body parts throughout their lifespan that can be attributed to strategic regulation of conserved signaling pathways by newt’s regeneration tool-kit genes. Here we report the use of a genetically tractable Drosophila eye model to demonstrate the regeneration potential of a group of unique protein(s) from newt (Notophthalmus viridescens), which when ectopically expressed can significantly rescue missing photoreceptor cells in a Drosophila eye mutant. These newt proteins with signal peptides motifs exhibit non-cell-autonomous rescue properties and their regeneration potential even extends into later stages of fly development. Ectopic expression of these newt genes can rescue eye mutant phenotype by promoting cell proliferation and blocking cell death. These novel newt genes downregulate the evolutionarily conserved Wingless (Wg)/Wnt signaling pathway to promote rescue. Modulation of Wg/Wnt signaling levels by using antagonists or agonists of Wg/Wnt signaling pathway in eye mutant background where newt gene(s) is ectopically expressed suggests that Wg signaling acts downstream of newt genes. Our data highlights the regeneration potential of novel newt proteins that regulate conserved pathways to trigger a robust regeneration response in Drosophila model with weak regeneration capability.

scholarly journals Activation of the Hedgehog and Wnt/β-Catenin Signaling Pathways in Basal Cell Carcinoma

2021 ◽  
pp. 506-512
Author(s):  
Tomoaki Takada
Keyword(s):  
Basal Cell Carcinoma ◽  
Wnt Signaling ◽  
Cell Carcinoma ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Basal Cell ◽  
Transcriptional Activation ◽  
Wnt Signaling Pathway ◽  
Downstream Effectors ◽  
Mrna Binding

In basal cell carcinoma (BCC) tumorigenesis, interaction between Hedgehog (Hh) and Wnt/β-catenin (Wnt) signaling pathways has been investigated, but not completely elucidated. Here, a case of sporadic BCC in an 80-year-old man is presented, and the effectiveness of SMO inhibitors in case of relapse is predicted. The aim of this study was to determine whether the SMO inhibitors can be effective in treating this individual should the tumor recur in the future. Immunohistochemistry (IHC) was performed in a tumor and the adjacent skin tissue from the patient. IHC within the same BCC tissue specimen revealed that Glioma-associated oncogene 1 (GLI1) and Smoothened (SMO) in the Hh signaling pathway and insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in the Wnt signaling pathway were overexpressed. Hh and Wnt signaling pathways were activated. These findings suggest that the patient might be resistant to treatment with SMO inhibitors because of the interaction between Hh and Wnt signaling pathways. Overexpression of GLI1 leads to transcriptional activation, making it an attractive molecular target for anticancer therapy owing to the downstream effectors of the cascade.

scholarly journals TMEM132A, a Novel Wnt Signaling Pathway Regulator Through Wntless (WLS) Interaction

2020 ◽  
Vol 8 ◽  
Author(s):  
Binbin Li ◽  
Lee A. Niswander
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathway ◽  
Transmembrane Protein ◽  
Wnt Signaling Pathway ◽  
Regulatory Mechanisms ◽  
Fundamental Aspect ◽  
Adult Tissue ◽  
Functional Interaction ◽  
Ligand Interaction ◽  
Wnt Signal

Wnt signaling pathway plays indispensable roles in embryonic development and adult tissue homeostasis. However, the regulatory mechanisms involved in Wnt ligand trafficking within and secretion from the signal sending cells is still relatively uncharacterized. Here, we discover a novel regulator of Wnt signaling pathway called transmembrane protein 132A (TMEM132A). Our evidence shows a physical and functional interaction of TMEM132A with the Wnt ligand transporting protein Wntless (WLS). We show that TMEM132A stabilizes Wnt ligand, enhances WLS–Wnt ligand interaction, and activates the Wnt signaling pathway. Our results shed new light on the cellular mechanism underlying the fundamental aspect of WNT secretion from Wnt signal sending cells.

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