| Full text | |
| Author(s): |
Zen Petisco Fiore, Ana Paula
;
Rodrigues, Ana Maria
;
Ribeiro-Filho, Helder Veras
;
Manucci, Antonio Carlos
;
de Freitas Ribeiro, Pedro
;
Silva Botelho, Mayara Carolinne
;
Vogel, Christine
;
Lopes-de-Oliveira, Paulo Sergio
;
Pagano, Michele
;
Bruni-Cardoso, Alexandre
Total Authors: 10
|
| Document type: | Journal article |
| Source: | BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS; v. 1866, n. 12, p. 11-pg., 2022-09-01. |
| Abstract | |
The Hippo pathway plays central roles in relaying mechanical signals during development and tumorigenesis, but how the proteostasis of the Hippo kinase MST2 is regulated remains unknown. Here, we found that chemical inhibition of proteasomal proteolysis resulted in increased levels of MST2 in human breast epithelial cells. MST2 binds SCF beta TrCP E3 ubiquitin ligase and silencing beta TrCP resulted in MST2 accumulation. Site-directed mutagenesis combined with computational molecular dynamics studies revealed that beta TrCP binds MST2 via a non-canonical degradation motif. Additionally, stiffer extracellular matrix, as well as hyperactivation of integrins resulted in enhanced MST2 degradation mediated by integrin-linked kinase (ILK) and actomyosin stress fibers. Our study uncovers the underlying biochemical mechanisms controlling MST2 degradation and underscores how alterations in the microenvironment rigidity regulate the proteostasis of a central Hippo pathway component. (AU) | |
| FAPESP's process: | 17/25437-3 - High-throughput identification of genes that mediate cell quiescence induced by laminin |
| Grantee: | Mayara Carolinne Silva Botelho |
| Support Opportunities: | Scholarships in Brazil - Doctorate |
| FAPESP's process: | 17/18641-3 - MST2 proteolysis as a mechanism to modulate HIPPO-YAP activity in breast epithelial cells |
| Grantee: | Ana Paula Zen Petisco Fiore |
| Support Opportunities: | Scholarships abroad - Research Internship - Post-doctor |
| FAPESP's process: | 18/00629-0 - Detection and characterization of protein cavities using parallel computing and molecular descriptors |
| Grantee: | Paulo Sergio Lopes de Oliveira |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 14/25832-1 - Hippo-YAP pathway as a mediator of extracellular matrix signals in non-malignant and malignant epithelial cells of the mammary gland |
| Grantee: | Ana Paula Zen Petisco Fiore |
| Support Opportunities: | Scholarships in Brazil - Post-Doctoral |
| FAPESP's process: | 14/10492-0 - Hippo-YAP as a converging pathway for biochemical and mechanical signals from the extracellular matrix during mammary gland morphogenesis and breast cancer progression |
| Grantee: | Alexandre Bruni Cardoso |
| Support Opportunities: | Research Grants - Young Investigators Grants |
| FAPESP's process: | 17/18067-5 - Investigation of the dynamics and function of nuclear actin in response to different mechanical signals and composition of the extracellular matrix |
| Grantee: | Pedro de Freitas Ribeiro |
| Support Opportunities: | Scholarships in Brazil - Doctorate (Direct) |
| FAPESP's process: | 19/26767-2 - Proteostasis regulation of MST2 in the Hippo pathway |
| Grantee: | Alexandre Bruni Cardoso |
| Support Opportunities: | Regular Research Grants |