Maspin - function and signaling pathways in the mouse mammary epithelium

• Grant number: 15/09309-0
• Support Opportunities: Regular Research Grants
• Start date: November 01, 2016
• End date: October 31, 2018
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Nathalie Cella
• Grantee: Nathalie Cella
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Julia Pinheiro Chagas da Cunha

Abstract

Maspin (SERPINB5) is a tumor and metastasis suppressor gene identified in the mammary tissue in a search for genes which are downregulated in tumors compared to the normal organ. Now it is known that this protein is expressed by most epithelia. Maspin has diverse biological activities including regulation of cell adhesion, migration, proliferation and cell death as well as control of gene expression via chromatin remodeling and regulation of oxidative stress response. Though evidences indicate maspin as a tumor suppressor, clinical studies brought controversies, since maspin expression is associated with a bad prognosis in several tumor types. New data suggest that maspin nuclear localization (as opposed to cytoplasmic and nuclear localization) is associated with a good prognosis and tumor suppression. These studies underscore the importance of understanding the role of maspin in the cell and how its subcellular localization is regulated. In addition, it is essential to investigate maspin function and the underlying molecular mechanism in physiological conditions in order to understand its malfunction in neoplasia. Our group verified that maspin is phosphorylated in the MCF-10A cell line and observed that this post-translational modification correlates with maspin cytoplasmic localization (Longhi & Cella 2012). We observed that maspin phosphorylation is regulated by the epithelial growth factor receptor (EGFR) signaling pathway and this phosphorylation is immediately followed by maspin nuclear translocation. In vivo, we observed maspin expression is restricted to the lactation and involution stages, whereas maspin phosphorylation could only be detected during lactation (Longhi et al 2016). These data suggest that maspin expression and phosphorylation are developmentally regulated in the mammary gland and it has a role in mammary epithelial cell differentiation. This research proposal intends to continue and deepen this study via the following objectives: (1) to determine maspin phosphorylation sites by mass spectrometry; (2) to determine which EGFR downstream effectors regulate maspin phosphorylation; (3) to investigate the molecular machinery involved in maspin nuclear translocation and (4) to investigate the role of maspin in the morphogenesis and function of the mammary gland in vitro and in vivo. (AU)

Scientific publications

(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)

REINA, JEFFREY; ZHOU, LIXIN; FONTES, MARCOS R. M.; PANTE, NELLY; CELLA, NATHALIE. Identification of a putative nuclear localization signal in the tumor suppressor maspin sheds light on its nuclear import regulation. FEBS OPEN BIO, v. 9, n. 7, p. 1174-1183, JUL 2019. (13/24705-3, 15/09309-0)

LONGHI, M. T.; SILVA, L. E.; PEREIRA, M.; MAGALHAES, M.; REINA, J.; VITORINO, F. N. L.; GUMBINER, B. M.; DA CUNHA, J. P. C.; CELLA, N.. PI3K-AKT, JAK2-STAT3 pathways and cell-cell contact regulate maspin subcellular localization. CELL COMMUNICATION AND SIGNALING, v. 19, n. 1, AUG 14 2021. (17/18344-9, 13/00815-4, 15/09309-0, 13/07467-1, 15/16384-8)