Home Blog of Signal Transduction Angiogenesis Src Axin phosphorylation in condensates counteracts tankyrase-mediated degradation

Category

Archives

Popular Post

ESKM, a novel therapeutic agent for sensitive and resistant PH+ leukemias

The mechanism of resistance to JAK2 inhibitor in myeloproliferative neoplasms patients

Effects of PARP inhibitors in BRCA gene-mutated ovarian cancer

DASATINIB; An inhibitor of Receptor Tyrosine Kinase

GP130/JAK/STAT3 signaling pathway induces multiple myeloma

Axin phosphorylation in condensates counteracts tankyrase-mediated degradation

Axin is a central negative regulator of the proto-oncogenic Wnt/β-catenin signaling pathway, as axin condensates provide a scaffold for the assembly of a multiprotein complex degrading β-catenin. Axin in turn is degraded via tankyrase. Consequently, small molecule tankyrase inhibitors block Wnt signaling by stabilizing axin, revealing potential for cancer therapy. Here, we discover phosphorylation of axin by casein kinase 1α (CK1α) at an N-terminal CK1 consensus motif, which was antagonized by protein phosphatase 1 (PP1). Axin condensates promoted phosphorylation by enriching CK1α over PP1. Importantly, the phosphorylation took place within the tankyrase-binding site, hindered axin-tankyrase interaction electrostatically and/or sterically, and counteracted tankyrase-mediated degradation of axin. Thus, the presented data propose a novel mechanism regulating axin stability, with implications for Wnt signaling, cancer therapy and self-organization of biomolecular condensates.

 

Comments:

The passage you provided describes a significant discovery related to the regulation of the Wnt/β-catenin signaling pathway and its potential implications for cancer therapy and biomolecular condensates. Here's a breakdown of the key points:

1. **Axin as a Negative Regulator**: Axin plays a crucial role as a central negative regulator of the Wnt/β-catenin signaling pathway. This pathway is often associated with oncogenesis (the development of cancer) when it is dysregulated.

2. **Axin Condensates**: Axin forms condensates that act as a scaffold for assembling a multiprotein complex responsible for degrading β-catenin. The degradation of β-catenin is a key step in preventing the activation of the Wnt signaling pathway.

3. **Degradation of Axin via Tankyrase**: Axin itself is subject to degradation, and this degradation is mediated by tankyrase.

4. **Tankyrase Inhibitors**: Small molecule inhibitors of tankyrase can block the Wnt signaling pathway by stabilizing axin. This stabilization prevents the degradation of axin, which, in turn, inhibits the activation of the Wnt pathway. This has potential implications for cancer therapy, as inhibiting Wnt signaling can be a strategy for treating certain types of cancer.

5. **Phosphorylation of Axin by CK1α**: The presented data reveal a novel mechanism involving the phosphorylation of axin by a kinase called casein kinase 1α (CK1α). This phosphorylation occurs at a specific N-terminal CK1 consensus motif.

6. **Antagonism by Protein Phosphatase 1 (PP1)**: The phosphorylation of axin by CK1α is antagonized by another protein called protein phosphatase 1 (PP1). PP1 appears to counteract the effects of CK1α phosphorylation.

7. **Enrichment of CK1α in Axin Condensates**: The axin condensates play a role in promoting the phosphorylation of axin by enriching CK1α and potentially limiting the activity of PP1. This suggests that the condensates themselves play a regulatory role in this process.

8. **Phosphorylation Hinders Tankyrase Interaction**: Importantly, the phosphorylation of axin by CK1α takes place within the tankyrase-binding site on axin. This phosphorylation appears to hinder the interaction between axin and tankyrase, possibly through electrostatic or steric effects.

9. **Counteraction of Tankyrase-Mediated Degradation**: As a result of this phosphorylation, axin is protected from tankyrase-mediated degradation. This means that the stabilization of axin through CK1α phosphorylation counteracts the degradation process initiated by tankyrase.

10. **Implications**: This discovery proposes a novel mechanism for regulating axin stability, which has implications for the Wnt signaling pathway, cancer therapy, and the self-organization of biomolecular condensates. It provides insights into how the Wnt pathway can be modulated and suggests potential therapeutic targets for cancer treatment.

In summary, this research sheds light on a previously unknown regulatory mechanism in the Wnt/β-catenin signaling pathway and offers potential avenues for cancer therapy by targeting this mechanism to stabilize axin and inhibit Wnt signaling. Additionally, it highlights the role of biomolecular condensates in cellular processes and signal regulation.

Related Products

Cat.No. Product Name Information
S7060 PP1 PP1 (AGL 1872, EI 275) is a potent and selective Src inhibitor for Lck/Fyn with IC50 of 5 nM/ 6 nM.

Related Targets

Src