scholarly journals Analysis of Endogenous LRP6 Function Reveals a Novel Feedback Mechanism by Which Wnt Negatively Regulates Its Receptor

2007 ◽  
Vol 27 (20) ◽  
pp. 7291-7301 ◽  
Author(s):  
Zahid Khan ◽  
Sapna Vijayakumar ◽  
Teresa Villanueva de la Torre ◽  
Sabrina Rotolo ◽  
Anna Bafico
Keyword(s):  
Wnt Signaling ◽  
Wnt Pathway ◽  
Mrna Level ◽  
Cellular Membrane ◽  
Feedback Mechanism ◽  
Bone Diseases ◽  
Dependent Manner ◽  
Direct Role ◽  
Initial Stimulus ◽  
Canonical Wnt

ABSTRACT The canonical Wnt pathway plays a crucial role in embryonic development, and its deregulation is involved in human diseases. The LRP6 single-span transmembrane coreceptor is essential for transmission of canonical Wnt signaling. However, due to the lack of immunological reagents, our understanding of LRP6 structure and function has relied on studies involving its overexpression, and regulation of the endogenous receptor by the Wnt ligand has remained unexplored. Using a highly sensitive and specific antibody to LRP6, we demonstrate that the endogenous receptor is modified by N-glycosylation and is phosphorylated in response to Wnt stimulation in a sustained yet ligand-dependent manner. Moreover, following triggering by Wnt, endogenous LRP6 is internalized and recycled back to the cellular membrane within hours of the initial stimulus. Finally, we have identified a novel feedback mechanism by which Wnt, acting through β-catenin, negatively regulates LRP6 at the mRNA level. Together, these findings contribute significantly to our understanding of LRP6 function and uncover a new level of regulation of Wnt signaling. In light of the direct role that the Wnt pathway plays in human bone diseases and malignancies, our findings may support the development of novel therapeutic approaches that target Wnt signaling through LRP6.

scholarly journals Regulation of Wnt Signaling by FOX Transcription Factors in Cancer

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3446
Author(s):  
Stefan Koch
Keyword(s):  
Transcription Factors ◽  
Wnt Signaling ◽  
Wnt Pathway ◽  
Treatment Options ◽  
Wnt Signaling Pathway ◽  
Tissue Homeostasis ◽  
Fine Tuning ◽  
Dependent Manner ◽  
Forkhead Box ◽  
Signaling Activity

Aberrant activation of the oncogenic Wnt signaling pathway is a hallmark of numerous types of cancer. However, in many cases, it is unclear how a chronically high Wnt signaling tone is maintained in the absence of activating pathway mutations. Forkhead box (FOX) family transcription factors are key regulators of embryonic development and tissue homeostasis, and there is mounting evidence that they act in part by fine-tuning the Wnt signaling output in a tissue-specific and context-dependent manner. Here, I review the diverse ways in which FOX transcription factors interact with the Wnt pathway, and how the ectopic reactivation of FOX proteins may affect Wnt signaling activity in various types of cancer. Many FOX transcription factors are partially functionally redundant and exhibit a highly restricted expression pattern, especially in adults. Thus, precision targeting of individual FOX proteins may lead to safe treatment options for Wnt-dependent cancers.

scholarly journals The Microphthalmia-Associated Transcription Factor Mitf Interacts with β-Catenin To Determine Target Gene Expression

2006 ◽  
Vol 26 (23) ◽  
pp. 8914-8927 ◽  
Author(s):  
Alexander Schepsky ◽  
Katja Bruser ◽  
Gunnar J. Gunnarsson ◽  
Jane Goodall ◽  
Jón H. Hallsson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Critical Role ◽  
Wnt Signaling Pathway ◽  
Feedback Mechanism ◽  
Canonical Wnt Signaling ◽  
Melanocyte Stem Cells ◽  
Canonical Wnt

ABSTRACT Commitment to the melanocyte lineage is characterized by the onset of expression of the microphthalmia-associated transcription factor (Mitf). This transcription factor plays a fundamental role in melanocyte development and maintenance and seems to be crucial for the survival of malignant melanocytes. Furthermore, Mitf has been shown to be involved in cell cycle regulation and to play important functions in self-renewal and maintenance of melanocyte stem cells. Although little is known about how Mitf regulates these various processes, one possibility is that Mitf interacts with other regulators. Here we show that Mitf can interact directly with β-catenin, the key mediator of the canonical Wnt signaling pathway. The Wnt signaling pathway plays a critical role in melanocyte development and is intimately involved in triggering melanocyte stem cell proliferation. Significantly, constitutive activation of this pathway is a feature of a number of cancers including malignant melanoma. Here we show that Mitf can redirect β-catenin transcriptional activity away from canonical Wnt signaling-regulated genes toward Mitf-specific target promoters to activate transcription. Thus, by a feedback mechanism, Mitf can diversify the output of canonical Wnt signaling to enhance the repertoire of genes regulated by β-catenin. Our results reveal a novel mechanism by which Wnt signaling and β-catenin activate gene expression, with significant implications for our understanding of both melanocyte development and melanoma.

Noncanonical Wnt5a Is Induced by HTLV-1 bZIP Factor, and Supports Proliferation and Migration of Adult T-Cell Leukemia Cell.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2405-2405
Author(s):  
Jun-ichirou Yasunaga ◽  
Guangyong Ma ◽  
Jun Fan ◽  
Masao Matsuoka
Keyword(s):  
T Cell ◽  
Wnt Signaling ◽  
Wnt Pathway ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Canonical Wnt Pathway ◽  
Bzip Factor ◽  
And Migration ◽  
Canonical Wnt

Abstract Abstract 2405 Adult T-cell leukemia (ATL) is a fatal malignancy of CD4-positive T-cells caused by human T-cell leukemia virus type1 (HTLV-1). HTLV-1 bZIP factor (HBZ) is encoded in the minus strand of HTLV-1 provirus, and is consistently expressed in HTLV-1-infected cells. It has been shown that HBZ promotes proliferation of T-cells, and HBZ-expressing transgenic mice develop T-cell lymphomas and systemic inflammations, suggesting that HBZ has the critical roles in pathogenesis of HTLV-1. However, the molecular mechanisms of HBZ-induced oncogenesis have not been clarified yet. The Wnt signaling is a highly conserved cellular signaling pathway in eukaryotes and the Wnt ligands have been found to trigger multiple pathways of Wnt signaling. The most well-studied cascade is the Wnt/β-catenin pathway (also known as the canonical Wnt pathway), which is β-catenin-dependent and mainly controls cell differentiation, proliferation, and apoptosis. Aberrant activation of the canonical Wnt pathway has been linked to many cancers. In contrast, it is known that the noncanonical Wnt pathway antagonizes the canonical pathway, while a representative noncanonical Wnt ligand, Wnt5a, is suggested to have both oncogenic and tumor suppressive properties in several malignancies. The significance of those Wnt pathways in HTLV-1-associated oncogenesis is still obscure. In this study, we found that HBZ markedly suppressed the canonical Wnt/β-catenin pathway. As a mechanism of HBZ-mediated Wnt suppression, we found that HBZ targets LEF1 and TCF1, the key transcription factors of the pathway, and impairs its DNA-binding ability. In contrast, HTLV-1 Tax protein interacted with Dvl and DAPLE, which are the regulators of the canonical Wnt signaling, and activated the pathway. Indeed, the canonical Wnt activation is not observed in ATL cells, and enforced activation of β-catenin in ATL cells inhibited cellular proliferation, implying that activation of the canonical Wnt pathway might have suppressive effect on ATL cells. On the other hand, HBZ induces the transcription of the noncanonical Wnt5a by enhancing its promoter activity. In addition, Wnt5a transcription level in ATL cells is significantly higher than in HTLV-1-uninifected control cells. Knockdown of Wnt5a impairs both proliferation and migration of ATL cells, suggesting that HBZ-induced Wnt5a supports development and progression of ATL. Our results implicate novel roles of HBZ in ATL leukemogenesis through dysregulation of both the canonical and noncanonical Wnt pathways. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A CRISPR knockout screen reveals new regulators of canonical Wnt signaling

Oncogenesis ◽  
2021 ◽  
Vol 10 (9) ◽  
Author(s):  
Tamar Evron ◽  
Michal Caspi ◽  
Michal Kazelnik ◽  
Yarden Shor-Nareznoy ◽  
Shir Armoza-Eilat ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Wnt Pathway ◽  
Signal Transduction Pathway ◽  
Rapid Identification ◽  
Initiation Factor ◽  
Canonical Wnt Signaling ◽  
New Genes ◽  
A Genome ◽  
Signaling Activation ◽  
Canonical Wnt

AbstractThe Wnt signaling pathways play fundamental roles during both development and adult homeostasis. Aberrant activation of the canonical Wnt signal transduction pathway is involved in many diseases including cancer, and is especially implicated in the development and progression of colorectal cancer. Although extensively studied, new genes, mechanisms and regulatory modulators involved in Wnt signaling activation or silencing are still being discovered. Here we applied a genome-scale CRISPR-Cas9 knockout (KO) screen based on Wnt signaling induced cell survival to reveal new inhibitors of the oncogenic, canonical Wnt pathway. We have identified several potential Wnt signaling inhibitors and have characterized the effects of the initiation factor DExH-box protein 29 (DHX29) on the Wnt cascade. We show that KO of DHX29 activates the Wnt pathway leading to upregulation of the Wnt target gene cyclin-D1, while overexpression of DHX29 inhibits the pathway. Together, our data indicate that DHX29 may function as a new canonical Wnt signaling tumor suppressor and demonstrates that this screening approach can be used as a strategy for rapid identification of novel Wnt signaling modulators.

Abstract 14: The Cytoskeletal Architecture of Myocytes Derived from Human Cardiac Progenitor Cells

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Francesco Pasqualini ◽  
Moises Di Sante ◽  
João D Pereira ◽  
Piero Anversa ◽  
Marcello Rota ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Progenitor Cells ◽  
Wnt Pathway ◽  
Cardiac Cells ◽  
Cardiac Progenitor Cells ◽  
Homogeneous Population ◽  
Cardiomyogenic Differentiation ◽  
Induced Pluripotent ◽  
Canonical Wnt

The stem cell antigen c-kit characterizes a heterogeneous pool of human cardiac progenitor cells (hCPCs) that exhibit a remarkable degree of regenerative potential and are currently employed in clinical trials. While this hCPC pool contains distinct subpopulations of c-kit+ cells that preferentially differentiate into muscular or vascular cardiac cells, we hypothesize that hCPCs may be coerced to specify only along the cardiomyogenic lineage by manipulating the Wnt/β-catenin pathway. We report that pharmacological inhibition of the non-canonical Wnt pathway facilitated the commitment of more than >95% c-kit+ hCPCs to the cardiomyocyte lineage after 4 days in-vitro: this constitutes a substantially more homogeneous population than previously reported with dexamethasone treatment. The hCPC-derived myocytes stained positive for Nkx2.5, a transcription factor that orchestrates cardiomyogenic differentiation, and for the contractile protein sarcomeric α-actin. To test if we could push the cells towards a more mature phenotype, we mimicked the cyclic modulation of the Wnt pathway observed during development. While activation of Wnt signaling resulted in widespread cell death and reduction in cell size, subsequent Wnt inhibition prompted the spared cells to proliferate. With this protocol, hCPC-derived myocytes increased in size and displayed more mature cytoskeletal architectures. In contrast with dexamethasone treated cells, where the localization of α-sarcomeric actinin is mostly diffuse in the cytoplasm, here we observed both Z-bodies and Z-disks like structures. The latter exhibited a periodicity of ~1.6 um and were clustered in larger, more aligned actin bundles. This finding suggests that the tension developed along these cytoskeletal components may play a role in the recruitment of sarcomeric proteins. In conclusion, Wnt signaling inhibition in hCPCs may be sufficient to obtain a homogeneous population of cells with features of myocytes, characterized by improved cytoskeletal organization than dexamethasone treated cells and similar to that observed in myocytes derived from human induced pluripotent stem cells.

scholarly journals R-Spondin Family Members Regulate the Wnt Pathway by a Common Mechanism

2008 ◽  
Vol 19 (6) ◽  
pp. 2588-2596 ◽  
Author(s):  
Kyung-Ah Kim ◽  
Marie Wagle ◽  
Karolyn Tran ◽  
Xiaoming Zhan ◽  
Melissa A. Dixon ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Wnt Pathway ◽  
Expression Patterns ◽  
Family Members ◽  
Wnt Signaling Pathway ◽  
Direct Consequence ◽  
Common Mechanism ◽  
Wnt Ligands ◽  
Canonical Wnt

The R-Spondin (RSpo) family of secreted proteins is implicated in the activation of the Wnt signaling pathway. Despite the high structural homology between the four members, expression patterns and phenotypes in knockout mice have demonstrated striking differences. Here we dissected and compared the molecular and cellular function of all RSpo family members. Although all four RSpo proteins activate the canonical Wnt pathway, RSpo2 and 3 are more potent than RSpo1, whereas RSpo4 is relatively inactive. All RSpo members require Wnt ligands and LRP6 for activity and amplify signaling of Wnt3A, Wnt1, and Wnt7A, suggesting that RSpo proteins are general regulators of canonical Wnt signaling. Like RSpo1, RSpo2-4 antagonize DKK1 activity by interfering with DKK1 mediated LRP6 and Kremen association. Analysis of RSpo deletion mutants indicates that the cysteine-rich furin domains are sufficient and essential for the amplification of Wnt signaling and inhibition of DKK1, suggesting that Wnt amplification by RSpo proteins may be a direct consequence of DKK1 inhibition. Together, these findings indicate that RSpo proteins modulate the Wnt pathway by a common mechanism and suggest that coexpression with specific Wnt ligands and DKK1 may determine their biological specificity in vivo.

scholarly journals Relaxin reverses maladaptive remodeling of the aged heart through Wnt-signaling

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Brian Martin ◽  
Beth Gabris ◽  
Amr F. Barakat ◽  
Brian L. Henry ◽  
Marianna Giannini ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Healthy Aging ◽  
Ventricular Myocytes ◽  
Therapeutic Potential ◽  
Electrical Remodeling ◽  
Dependent Manner ◽  
Aged Rats ◽  
Canonical Wnt ◽  
Dickkopf 1 ◽  
Fundamental Mechanism

AbstractHealthy aging results in cardiac structural and electrical remodeling that increases susceptibility to cardiovascular diseases. Relaxin, an insulin-like hormone, suppresses atrial fibrillation, inflammation and fibrosis in aged rats but the mechanisms-of-action are unknown. Here we show that relaxin treatment of aged rats reverses pathological electrical remodeling (increasing Nav1.5 expression and localization of Connexin43 to intercalated disks) by activating canonical Wnt signaling. In isolated adult ventricular myocytes, relaxin upregulated Nav1.5 (EC50 = 1.3 nM) by a mechanism inhibited by the addition of Dickkopf-1. Furthermore, relaxin increased the levels of connexin43, Wnt1, and cytosolic and nuclear β-catenin. Treatment with Wnt1 or CHIR-99021 (a GSK3β inhibitor) mimicked the relaxin effects. In isolated fibroblasts, relaxin blocked TGFβ-induced collagen elevation in a Wnt dependent manner. These findings demonstrate a close interplay between relaxin and Wnt-signaling resulting in myocardial remodeling and reveals a fundamental mechanism of great therapeutic potential.

The canonical Wnt signaling pathway promotes chondrocyte differentiation in a Sox9-dependent manner

2005 ◽  
Vol 333 (4) ◽  
pp. 1300-1308 ◽  
Author(s):  
Fumiko Yano ◽  
Fumitaka Kugimiya ◽  
Shinsuke Ohba ◽  
Toshiyuki Ikeda ◽  
Hirotaka Chikuda ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Chondrocyte Differentiation ◽  
Dependent Manner ◽  
Canonical Wnt Signaling ◽  
Canonical Wnt

scholarly journals Multiple Wnts act synergistically to induce Chk1/Grapes expression and mediate G2 arrest in Drosophila tracheoblasts

2020 ◽  
Author(s):  
Amrutha Kizhedathu ◽  
Rose Sebastian Kunnappallil ◽  
Archit V Bagul ◽  
Puja Verma ◽  
Arjun Guha
Keyword(s):  
Wnt Signaling ◽  
Kinase Activity ◽  
Developmental Regulation ◽  
Wnt Signalling ◽  
Dependent Manner ◽  
G2 Arrest ◽  
Tracheal System ◽  
G2 Phase ◽  
Canonical Wnt ◽  
Atr Kinase

ABSTRACTLarval tracheae of Drosophila harbor progenitors of the adult tracheal system (tracheoblasts). Thoracic tracheoblasts are arrested in the G2 phase of the cell cycle in an ATR (mei-41)-Checkpoint Kinase1 (grapes, Chk1) dependent manner prior to mitotic re-entry. Here we investigate developmental regulation of Chk1 activation. We report that Wnt signaling is high in tracheoblasts and is necessary for high levels of activated (phosphorylated) Chk1. We find that canonical Wnt signaling facilitates this by transcriptional upregulation of Chk1 expression in cells that have ATR kinase activity. Wnt signalling is dependent on four Wnts (Wg, Wnt5, 6,10) that are expressed at high levels in arrested tracheoblasts and downregulated at mitotic re-entry. Interestingly, none of the Wnts are dispensable and act synergistically to induce Chk1. Finally, we show that downregulation of Wnt signalling and Chk1 expression leads to mitotic re-entry and the concomitant upregulation of Dpp signalling, driving tracheoblast proliferation.

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