Proteostasis regulation of MST2 in the Hippo pathway

• Grant number: 19/26767-2
• Support Opportunities: Regular Research Grants
• Start date: May 01, 2020
• End date: October 31, 2022
• Field of knowledge: Biological Sciences - Biochemistry
• Principal Investigator: Alexandre Bruni Cardoso
• Grantee: Alexandre Bruni Cardoso
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The Hippo pathway plays central roles in the regulation of cell proliferation, apoptosis, organ size control, mechanotransduction and in turmorigenesis. In mammalians, Hippo consists fundamentally in 4 serine-threonine quinases: Mammalian Ste-20-like Kinase 1/2 (MST1, MST2) and large tumor suppressor 1/2 (LATS1, LATS2). Hippo activation culminates with phosphorylation, cytoplasmic retention and inactivation of the transcription co-activators YAP and TAZ. When Hippo is inactive, dephosphorylated YAP/TAZ enter the nucleus resulting in increased proliferation and malignant progression in epithelial cells. Nevertheless, the proteostasis regulation of the Hippo kinases and how that affects mammary tumors are poorly understood. Preliminary results from our laboratory indicate that the level of MST2 is regulated by proteasome degradation activated by the integrin-ILK axis signaling in a E3-ligase SCF²TrCP - dependent manner. Furthermore, we have observed that mammary gland malignant cells express a novel splicing variant of STK/MST2 which is translated into a protein more susceptible to degradation. In this project, we propose to dissect the molecular basis underlying the degradation of MST2 and of its new proteoform by using genetic, biochemical and microscopy tools and also 2D and 3D cell cultures. The conclusion of these studies has the potential to unveil key aspects of the Hippo pathway and its role in Breast Cancer. (AU)

Scientific publications

(6)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

TOMASIN, REBEKA; BRUNI-CARDOSO, ALEXANDRE. The role of cellular quiescence in cancer - beyond a quiet passenger. Journal of Cell Science, v. 135, n. 15, p. 11-pg., 2022-08-01. (19/26767-2)

GLEZER, ISAIAS; BRUNI-CARDOSO, ALEXANDRE; SCHECHTMAN, DEBORAH; MALNIC, BETTINA. Viral infection and smell loss: The case of COVID-19. Journal of Neurochemistry, v. 157, n. 4, p. 930-943, MAY 2021. (19/26767-2, 19/06982-6, 13/07937-8, 18/18633-3)

SBRANA, MARIANA FERREIRA; FORNAZIERI, MARCO AURELIO; BRUNI-CARDOSO, ALEXANDRE; AVELINO-SILVA, I, VIVIAN; SCHECHTMAN, DEBORAH; VOEGELS, RICHARD LOUIS; MALNIC, BETTINA; GLEZER, ISAIAS; PINNA, FABIO DE REZENDE. Olfactory Dysfunction in Frontline Health Care Professionals During COVID-19 Pandemic in Brazil. FRONTIERS IN PHYSIOLOGY, v. 12, MAR 9 2021. (18/18633-3, 19/06982-6, 16/24471-0, 13/07937-8, 19/26767-2)

CERQUEIRA, OTTO LUIZ DUTRA; BOTELHO, MAYARA CAROLLINE SILVA; FIORE, ANA PAULA ZEN PETISCO; OSORIO, CYNTHIA APARECIDA BUENO DE TOLEDO; TOMASIN, REBEKA; MORAIS, MAURO CESAR CAFUNDO; LOPEZ, ROSSANA VERONICA MENDOZA; CARDOSO, ELAINE CRISTINA; VILELLA-ARIAS, SANTIAGO ANDRES; REIS, EDUARDO MORAES; et al. Prognostic value of integrin alpha V expression and localization pattern in invasive breast carcinomas. NEOPLASIA, v. 30, p. 13-pg., 2022-08-01. (14/10492-0, 17/25437-3, 14/25832-1, 19/26767-2)

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. Extracellular matrix stiffness regulates degradation of MST2 via SCF beta TrCP. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, v. 1866, n. 12, p. 11-pg., 2022-09-01. (17/25437-3, 17/18641-3, 18/00629-0, 14/25832-1, 14/10492-0, 17/18067-5, 19/26767-2)

RUSSO, LILIAN CRISTINA; TOMASIN, REBEKA; MATOS, ISAAC ARAUJO; MANUCCI, ANTONIO CARLOS; SOWA, SVEN T.; DALE, KATIE; CALDECOTT, KEITH W.; LEHTIO, LARI; SCHECHTMAN, DEBORAH; MEOTTI, FLAVIA C.; et al. The SARS-CoV-2 Nsp3 macrodomain reverses PARP9/DTX3L-dependent ADP-ribosylation induced by interferon signaling. Journal of Biological Chemistry, v. 297, n. 3, SEP 2021. (18/18007-5, 18/14898-2, 19/26767-2)