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GRASP pathway involving on the protein disulfide isomerase externalization and its implication in endothelial cell response

Grant number: 15/06210-2
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): September 01, 2015
Effective date (End): June 30, 2018
Field of knowledge:Biological Sciences - Biophysics - Cellular Biophysics
Principal researcher:Francisco Rafael Martins Laurindo
Grantee:Thaís Larissa Araujo de Oliveira Silva
Home Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Associated scholarship(s):17/01130-6 - Mechanisms and implications of selective cell-surface Grp94 inhibition in breast cancer cells, BE.EP.PD


Protein disulfide isomerase (PDI AI or PDI) is an important chaperone that acts in the oxidative folding in the endoplasmic reticulum with emerging role in signaling and redox homeostasis pathways, including NADPH oxidases interaction. A specific pool PDI presents in the extracellular space of several cell types and regulates processes like thrombosis, cell adhesion, viral infection and vascular remodeling. This pool, denominate PDI epi/pericelullar (pecPDI), modulates thiol redox reactions thats regulates: integrins, thrombospondin, metalloproteases, galectin 9, glycoprotein gp120 of HIV virus and tissue factor. The interaction between pecPDI and integrins (an important mecanosensor) and redox role of pecPDI suggest a possible modulation by pecPDI of shear stress responses in endothelial cells. Our group investigated PDI externalization and recently identify a pathway Golgi independent involving GRASP, a newly described protein as unconventional secretion pathway. Our hypothesis is that in response to shear stress in endothelial cells, the pecPDI is externalized by GRASP pathway and, in addition with others potential actions of GRASP, acts like integrate mechanism of mechanotransduction. We investigate the effect of GRASP-pecPDI pathway on activation of integrins and cytoskeleton organization, like associate subcellular mechanisms, in response to laminar shear stress in endothelial cells. In this way, we evaluate, in response to laminar shear stress: kinetics of PDI externalization, proteins that interact with PDI on the cell surface, PDI effects on the integrins activation, redox state changes of integrins and PDI, effects of gain loss function GRASP55/65 and GRASP phosphorylation of GRASP. These data must contribute to integrate understanding of mechanotransduction pathway in endothelial cells, provide conceptual advances and physiopathological implications.

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Scientific publications (4)
(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)
TANAKA, LEONARDO Y.; ARAUJO, THAIS L. S.; RODRIGUEZ, I, ANDRES; FERRAZ, MARIANA S.; PELEGATI, VITOR B.; MORAIS, MAURO C. C.; DOS SANTOS, ALINE M.; CESAR, CARLOS L.; RAMOS, ALEXANDRE F.; ALENCAR, ADRIANO M.; et al. Peri/epicellular protein disulfide isomerase-A1 acts as an upstream organizer of cytoskeletal mechanoadaptation in vascular smooth muscle cells. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, v. 316, n. 3, p. H566-H579, . (13/17115-5, 13/07937-8, 15/06210-2)
ARAUJO, THAIS L. S.; FERNANDES, CAROLINA G.; LAURINDO, FRANCISCO R. M.. Golgi-independent routes support protein disulfide isomerase externalization in vascular smooth muscle cells. REDOX BIOLOGY, v. 12, p. 1004-1010, . (13/07937-8, 15/06210-2, 12/02372-0)
SALIBE-FILHO, WILLIAM; ARAUJO, THAIS L. S.; MELO, EVERTON G.; COIMBRA, LUIZA B. C. T.; LAPA, MONICA S.; ACENCIO, MILENA M. P.; FREITAS-FILHO, ORIVAL; CAPELOZZI, VERA LUIZA; TEIXEIRA, LISETE RIBEIRO; FERNANDES, CAIO J. C. S.; et al. Shear stress-exposed pulmonary artery endothelial cells fail to upregulate HSP70 in chronic thromboembolic pulmonary hypertension. PLoS One, v. 15, n. 12, . (20/11249-3, 19/20435-8, 15/06210-2, 18/13739-8, 13/07937-8)
ARAUJO, THAIS L. S.; VENTURINI, GABRIELA; MORETTI, ANA I. S.; TANAKA, LEONARDO Y.; PEREIRA, ALEXANDRE COSTA; LAURINDO, FRANCISCO R. M.. Cell-surface HSP70 associates with thrombomodulin in endothelial cells. CELL STRESS & CHAPERONES, v. 24, n. 1, p. 273-282, . (13/07937-8, 15/06210-2)

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