The E3 Ubiquitin Ligase Deltex Regulates Wingless Gradient Formation and Signaling through Armadillo/β-Catenin Degradation

Concepts de base

The E3 ubiquitin ligase Deltex (Dx) regulates Wingless (Wg) signaling in Drosophila by facilitating the spreading of the Wg gradient and promoting the proteasomal degradation of the Wg effector Armadillo/β-catenin.

Résumé

The study investigates the role of the E3 ubiquitin ligase Deltex (Dx) in the regulation of Wingless (Wg) signaling in Drosophila. The key findings are:

1. Dx genetically interacts with components of the Wg signaling pathway, including the Wg ligand, its receptor Frizzled, and the transcriptional effector Armadillo (Arm).

2. Loss of Dx reduces the Wg gradient and the expression of Wg target genes, while overexpression of Dx expands the Wg gradient and affects the expression of short-range and long-range Wg targets.

3. Dx facilitates the endocytosis and trafficking of Wg, which contributes to the regulation of the Wg gradient.

4. Dx directly interacts with and promotes the proteasomal degradation of Arm, the Drosophila homolog of β-catenin, a key effector of Wg signaling.

5. The human homolog of Dx, DTX1, also binds to and facilitates the degradation of β-catenin, suggesting a conserved mechanism of Wg/Wnt signaling regulation.

The study highlights the multifaceted role of Dx in modulating Wg signaling, both at the level of Wg gradient formation and Arm/β-catenin stability, thereby providing insights into the regulation of this crucial developmental signaling pathway.

Stats

Dx overexpression with en-GAL4 results in a significant reduction in the expression of the Wg target genes Senseless and Cut.
Dx overexpression with en-GAL4 leads to a marked decrease in the accumulation of the Wg effector Armadillo (Arm) in the wing imaginal disc.
Proteasome inhibitor MG132 treatment rescues the Dx-mediated downregulation of Arm in wing imaginal discs.
Overexpression of Dx in HEK-293 cells leads to a reduction in the levels of β-catenin, which is rescued by MG132 treatment.

Citations

"Dx over-expression with en-GAL4 shows pupal lethality at 25°C, however, at 18°C, the flies emerge with massive morphological defects."
"Dx over-expression in the thorax leads to reduced and disoriented macrochaetae and reduction in scutellar bristles."
"Dx over-expression in the leg results in a reduced tarsal segment along the proximodistal axis and dorsoventral shift of the sex combs."

Idées clés tirées de

E3 ubiquitin ligase Deltex facilitates the expansion of Wingless gradient and antagonizes Wingless signaling through a conserved mechanism of transcriptional effector Armadillo/β-catenin degradation

by Sharma,V., S... à www.biorxiv.org 06-07-2023

https://www.biorxiv.org/content/10.1101/2023.06.06.543920v2

Questions plus approfondies

How might the regulation of Wg signaling by Dx be integrated with its known roles in other signaling pathways, such as Notch and JNK?

Dx plays a crucial role in the regulation of multiple signaling pathways, including Wg, Notch, and JNK. In the context of Wg signaling, Dx facilitates the spreading of the Wg gradient and directly affects the stability of Arm/β-catenin. This regulation of Wg signaling by Dx can be integrated with its roles in other pathways through crosstalk and coordination of signaling events.
In the Notch pathway, Dx is known to regulate Notch signaling positively by modulating the endocytosis and trafficking of Notch receptors. The interaction between Dx and Notch leads to the accumulation of Notch in endocytic vesicles, affecting Notch signaling output. The regulation of Notch by Dx may intersect with Wg signaling, as Notch signaling is known to regulate the activity and accumulation of active β-catenin, the effector molecule in the Wg pathway. Therefore, Dx-mediated regulation of Notch and Wg signaling may be interconnected, influencing cellular responses to developmental cues.
Similarly, in the JNK pathway, Dx has been shown to synergize with JNK ligands and TRAF6 to activate JNK signaling. JNK signaling is involved in various cellular processes, including cell proliferation, apoptosis, and stress responses. The integration of JNK signaling with Wg signaling through Dx may involve the modulation of common downstream targets or the coordination of cellular responses to different stimuli. The crosstalk between Wg, Notch, and JNK pathways mediated by Dx highlights the complexity and interconnectedness of signaling networks in cellular regulation and development.

How might the regulation of Wg signaling by Dx be integrated with its known roles in other signaling pathways, such as Notch and JNK?

The conserved mechanism of Dx/DTX1-mediated regulation of Wnt/β-catenin signaling in human diseases, such as cancer, has significant implications for understanding disease pathogenesis and developing targeted therapies. Dysregulation of the Wnt/β-catenin pathway is a hallmark of various cancers, including colorectal cancer, Wilms tumor, and leukemia. The involvement of Dx/DTX1 in the degradation of β-catenin suggests a potential therapeutic target for modulating aberrant Wnt signaling in cancer.
In cancer, aberrant activation of the Wnt/β-catenin pathway leads to uncontrolled cell proliferation, invasion, and metastasis. Targeting key regulators of Wnt signaling, such as Dx/DTX1, offers a promising approach to inhibit the oncogenic effects of dysregulated Wnt signaling. By understanding the conserved mechanism of Dx/DTX1 in degrading β-catenin, researchers can develop targeted therapies that specifically modulate Wnt signaling in cancer cells, potentially leading to novel treatment strategies for cancer patients.
The conserved role of Dx/DTX1 in regulating Wnt/β-catenin signaling also provides insights into the molecular mechanisms underlying cancer development and progression. By elucidating the precise mechanisms by which Dx/DTX1 mediates β-catenin degradation, researchers can uncover new therapeutic targets and strategies for combating Wnt-driven cancers. Overall, the conserved Dx/DTX1-mediated regulation of Wnt/β-catenin signaling holds great promise for the development of targeted therapies for cancer treatment.

How might the regulation of Wg signaling by Dx be integrated with its known roles in other signaling pathways, such as Notch and JNK?

The Dx-mediated modulation of the Wg gradient and Arm/β-catenin stability presents exciting opportunities for therapeutic interventions targeting aberrant Wnt signaling in various diseases, including cancer. The regulation of the Wg gradient by Dx, leading to the proper activation of short-range and long-range target genes, highlights its potential as a therapeutic target for modulating Wnt signaling in disease states.
In cancer, where dysregulated Wnt signaling is a common feature, targeting Dx to modulate the Wg gradient and Arm/β-catenin stability could offer a novel approach to inhibit oncogenic signaling pathways. By manipulating Dx activity to control the spread of the Wg gradient and stabilize Arm/β-catenin, researchers may be able to disrupt the aberrant Wnt signaling cascade in cancer cells, leading to growth inhibition and potentially inducing apoptosis in tumor cells.
Furthermore, the conserved mechanism of Dx-mediated regulation of Wnt signaling, as demonstrated by the interaction of human DTX1 with β-catenin, opens up possibilities for developing targeted therapies that exploit this pathway for therapeutic interventions. By understanding the molecular mechanisms underlying Dx-mediated modulation of Wg signaling, researchers can design specific inhibitors or activators to fine-tune Wnt signaling in disease contexts, offering new avenues for precision medicine approaches in cancer and other Wnt-related disorders.