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The role of the scaffold protein RACK1 in Ca2+ signaling in mast cells

Grant number: 16/21988-2
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): June 12, 2017
Effective date (End): November 15, 2017
Field of knowledge:Biological Sciences - Morphology - Cytology and Cell Biology
Principal researcher:Maria Célia Jamur
Grantee:Edismauro Garcia Freitas Filho
Supervisor abroad: Indu S. Ambudkar
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Research place: National Institutes of Health, Bethesda (NIH), United States  
Associated to the scholarship:15/16673-0 - The role of the scaffold protein RACK1 in mast cell activation, BP.DR

Abstract

Mast cells are immunoregulatory cells that participate in various events such as asthma, allergy, and inflammation. The action of mast cells is directly related to their activation and subsequent release of various chemical mediators. Activation via the high affinity IgE receptor, FcµRI, is the best characterized form of mast cell activation that results in mediator secretion. Mediator release by mast cells depends on the increase in intracellular Ca2+ concentration, and on the entry of extracellular Ca2+. Although previous studies have demonstrated the basic mechanism involved in mast cell activation, the function of some regulatory proteins related to Ca2+ signaling in mast cells is still unknown. RACK1 (receptor for activated C kinase 1) is required as a scaffold protein for several proteins that are known to engage in Ca2+ signaling and mast cell activation. Previous studies have shown that RACK1 participates in the Ca2+-dependent activation of some immune cells and could play a very important role in asthma. Recently, for the first time, our laboratory has identified RACK1 in mast cells. Preliminary results show that after RBL-2H3 mast cell activation via FcµRI, the majority of RACK1 was translocated from the cytoplasm to the nucleus. However, some RACK1 remained adjacent to the plasma membrane. ShRNA mediated depletion of the RACK1 in RBL-2H3 mast cells resulted in a significant increase in the release of the preformed mediator b-hexosaminidase after activation via FcµRI or via Ca2+ entry stimulated by calcium ionophore. These findings suggest that RACK1 is a previously undescribed regulator of mast cell degranulation and may be involved in calcium signaling pathway in mast cells. The present study aims to characterize the functional role of RACK1 in Ca2+ signaling in mast cells. The interaction of RACK1 with Ca2+ signaling proteins will be explored in order to determine the role of RACK1 in Ca2+ regulation. ShRNA RBL-2H3 mast cells will be used to investigate the role of RACK1 in Ca2+ signaling. The role of RACK1 in Ca2+ mobilization will be analyzed in IP3-mediated Ca2+ release from endoplasmic reticulum stores and on the activation of store-operated Ca2+ entry (SOCE) after FcµRI activation. The effect of expression of RACK1 on SOCE will be also assessed independently of PLCg-mediated Ca2+ release from endoplasmic reticulum stores by stimulating cells with thapsigargin. An understanding of the role of RACK1 in Ca2+ signaling in mast cells may lead to new therapeutic targets for allergic and inflammatory process.

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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)
FREITAS FILHO, EDISMAURO G.; DA SILVA, ELAINE Z. M.; ONG, HWEI LING; SWAIM, WILLIAM D.; AMBUDKAR, INDU S.; OLIVER, CONSTANCE; JAMUR, MARIA CELIA. RACK1 plays a critical role in mast cell secretion and Ca2+ mobilization by modulating F-actin dynamics. Journal of Cell Science, v. 134, n. 9 MAY 2021. Web of Science Citations: 1.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.