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PLEKHA7 defines an apical junctional complex with cytoskeletal associations and miRNA-mediated growth implications
Antonis Kourtidis1, Panos Z Anastasiadis1
1a Department of Cancer Biology , Mayo Clinic Comprehensive Cancer, Center, Mayo Clinic , Jacksonville , FL , USA.
Insights
PLEKHA7 protein maintains epithelial integrity by regulating cytoskeletal dynamics and microRNA (miRNA)-mediated growth. Its loss impacts actin regulation and oncogenic miRNA levels, suggesting roles in cancer.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- E-cadherin-p120 catenin complexes are crucial for adherens junction (AJ) formation and epithelial cell structure.
- PLEKHA7, a component of these complexes, tethers microtubules to AJs, maintaining their integrity.
- PLEKHA7's role in regulating cellular behavior via microRNAs (miRNAs) at the apical zonula adherens (ZA) has been recently uncovered.
Purpose of the Study:
- To investigate novel PLEKHA7 interacting partners at the apical ZA.
- To elucidate the mechanisms by which PLEKHA7 influences cytoskeletal dynamics and miRNA regulation.
- To explore the implications of PLEKHA7's function in cancer.
Main Methods:
- Proteomic analysis to identify PLEKHA7 interacting partners.
- Biochemical assays to confirm protein associations.
- Studies on actin regulator cofilin activation and phosphatase PP1α interaction.
- Investigation of miR-19a regulation by PLEKHA7.
Main Results:
- PLEKHA7 associates with cytoskeletal proteins and RNA-binding proteins at the apical ZA.
- PLEKHA7 loss activates cofilin in a p120-dependent manner and is linked to PP1α.
- PLEKHA7 regulates the levels of oncogenic miR-19a.
Conclusions:
- PLEKHA7 plays a multi-layered role in integrating cytoskeletal dynamics and miRNA-mediated growth control at the ZA.
- These findings highlight PLEKHA7's critical involvement in maintaining epithelial integrity and suggest its potential role in cancer development.
- Further research into PLEKHA7's functions is warranted due to its implications in cancer.
Abstract:
E-cadherin-p120 catenin complexes are essential for adherens junction (AJ) formation and for the maintenance of the normal epithelial phenotype. PLEKHA7 was originally identified as a member of this complex that tethers microtubules to the AJs and supports their overall integrity. Recently, we revealed that PLEKHA7 regulates cellular behavior via miRNAs by associating with the microprocessor complex at the apical zonula adherens (ZA). We have also identified a new set of PLEKHA7 interacting partners at the apical ZA, via proteomics. Our analysis shows that the main groups of proteins associating with PLEKHA7 are cytoskeletal-related and RNA-binding proteins. Here, we provide extended evidence for association of PLEKHA7 with several of these proteins. We also show that PLEKHA7 loss activates the actin regulator cofilin in a p120-dependent manner, providing an explanation for the effects of PLEKHA7 on the cortical actin ring. Interestingly, PLEKHA7 regulates the levels and associates with PP1α, a phosphatase responsible for cofilin activation. Finally, we clarify the mode of regulation of the oncogenic miR-19a by PLEKHA7. Overall, our findings support a multi-layered role of PLEKHA7 in converging cytoskeletal dynamics and miRNA-mediated growth regulation at the ZA, with potentially critical implications in cancer that warrant further investigation.