Maspin in cell stress response and intercellular communication

• Grant number: 21/12268-4
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2022
• End date: August 31, 2024
• Field of knowledge: Biological Sciences - Biochemistry
• Principal Investigator: Nathalie Cella
• Grantee: Nathalie Cella
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Maspin is an abundant protein in epithelia, and it has diverse biological functions. In the organism, maspin inhibits angiogenesis, tumor cell growth and invasion. Maspin deficiency results in lethality during embryogenesis. Though most studies have observed that maspin is a tumor suppressor gene, clinical studies suggest that maspin can be an oncogene or a tumor suppressor if it is found in the cytoplasm or in the nucleus, respectively. Our group investigates the molecular mechanism underlying maspin cellular function and its alterations in neoplasia, with focus on the mammary gland development and breast cancer. Given several evidence indicating that maspin subcellular localization is determinant for its function in the cell, we sought to understand how this localization is regulated. We identified a putative nuclear localization signal in maspin and observed that maspin localization is regulated by a crosstalk between the EGF receptor (EGFR) pathway and cell-cell interaction. Since the EGFR pathway takes part of numerous cell processes, we investigated in which of them maspin is involved. For this purpose, maspin ligands were identified in EGF-treated MCF-10A cells by proteomic and interactome analyses. Most maspin ligands are proteins which takes part of the assembly and/or function of stress granules. In homeostasis (i.e., lack of stress), the identified proteins act on protein folding, protein translation, RNA processing and DNA damage response. In addition, other maspin ligands have a role in cell-cell contact and communication. This project will investigate the physical and functional interaction between maspin and three selected ligands, looking to understand how these interactions are related to cell stress response and juxtacrine signaling (contact-dependent signaling). These ligands are the TRiC (TCP-1 ring) complex, which is essential for protein folding; NDRG1 (N-myc downstream-regulated gene 1), a protein of the intercellular junction which modulates signaling to the nucleus and hnRNPs (heterogeneous nuclear ribonucleoproteins), which regulate pre-mRNA processing in the nucleus and the DNA damage response. These analyses will be extended for the pre-tumoral MCF10T and tumoral MCF10ACA isogenic models. This project may unravel how maspin acts in so many different processes in the cell and how these processes are subverted during tumor progression. (AU)