Extracellular matrix stiffness regulates degradation of MST2 via SCF βTrCP .

Autor: Fiore APZP; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo 05508-000, Brazil; Department of Biology, New York University, New York, NY 10003, USA., Rodrigues AM; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo 05508-000, Brazil., Ribeiro-Filho HV; Laboratório Nacional de Biociências, Centro Nacional de Pesquisa em Energia e Materiais, Campinas 13083-970, Brazil., Manucci AC; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo 05508-000, Brazil., de Freitas Ribeiro P; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo 05508-000, Brazil., Botelho MCS; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo 05508-000, Brazil., Vogel C; Department of Biology, New York University, New York, NY 10003, USA., Lopes-de-Oliveira PS; Laboratório Nacional de Biociências, Centro Nacional de Pesquisa em Energia e Materiais, Campinas 13083-970, Brazil., Pagano M; Department of Biochemistry and Molecular Pharmacology, Howard Hughes Medical Institute, New York University Grossman School of Medicine, New York, NY 10016, USA., Bruni-Cardoso A; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo 05508-000, Brazil. Electronic address: brunicar@iq.usp.br.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. General subjects [Biochim Biophys Acta Gen Subj] 2022 Dec; Vol. 1866 (12), pp. 130238. Date of Electronic Publication: 2022 Aug 28.
DOI: 10.1016/j.bbagen.2022.130238
Abstrakt: 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 βTrCP E3 ubiquitin ligase and silencing βTrCP resulted in MST2 accumulation. Site-directed mutagenesis combined with computational molecular dynamics studies revealed that βTrCP 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.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Michele Pagano reports a relationship with Coho Therapeutics that includes: equity or stocks. Michele Pagano reports a relationship with CullGen that includes: board membership. Michele Pagano reports a relationship with Kymera Therapeutics that includes: board membership. Michele Pagano reports a relationship with SEED Therapeutics that includes: board membership. Michele Pagano reports a relationship with Santi Therapeutics that includes: consulting or advisory. M.P. is a consultant for and has financial interests in Coho Therapeutics, CullGen, Kymera Therapeutics, and SEED Therapeutics. M.P. is a cofounder of Coho Therapeutics, is on the SAB of CullGen and Kymera Therapeutics, and is a consultant for Santi Therapeutics. The other authors declare no competing interests.
(Copyright © 2022 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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