Focal Adhesion Kinase Regulation of Mechanotransduction and its Impact on Endothelial Cell Functions

ABSTRACT The signaling pathways triggered by adherence of Candida albicans to the host cells or extracellular matrix are poorly understood. We provide here evidence in C. albicans yeasts of a p105 focal adhesion kinase (Fak)-like protein (that we termed CaFak), antigenically related to the vertebrate p125Fak, and its involvement in integrin-like-mediated fungus adhesion to vitronectin (VN) and EA.hy 926 human endothelial cell line. Biochemical analysis with different anti-chicken Fak antibodies identified CaFak as a 105-kDa protein and immunofluorescence and cytofluorimetric analysis on permeabilized cells specifically stain C. albicans yeasts; moreover, confocal microscopy evidences CaFak as a cytosolic protein that colocalizes on the membrane with the integrin-like VN receptors upon yeast adhesion to VN. The protein tyrosine kinase (PTK) inhibitors genistein and herbimycin A strongly inhibited C. albicans yeast adhesion to VN and EA.hy 926 endothelial cells. Moreover, engagement of αvβ3 and αvβ5 integrin-like on C. albicans either by specific monoclonal antibodies or upon adhesion to VN or EA.hy 926 endothelial cells stimulates CaFak tyrosine phosphorylation that is blocked by PTK inhibitor. A role for CaFak in C. albicans yeast adhesion was also supported by the failure of VN to stimulate its tyrosine phosphorylation in a C. albicans mutant showing normal levels of CaFak and VNR-like integrins but displaying reduced adhesiveness to VN and EA.hy 926 endothelial cells. Our results suggest that C. albicans Fak-like protein is involved in the control of yeast cell adhesion to VN and endothelial cells.

Download Full-text

Association of Low Tumor Endothelial Cell pY397–Focal Adhesion Kinase Expression With Survival in Patients With Neoadjuvant-Treated Locally Advanced Breast Cancer

JAMA Network Open ◽

10.1001/jamanetworkopen.2020.19304 ◽

2020 ◽

Vol 3 (10) ◽

pp. e2019304

Author(s):

Marina Roy-Luzarraga ◽

Tarek Abdel-Fatah ◽

Louise E. Reynolds ◽

Andrew Clear ◽

Joseph G. Taylor ◽

...

Keyword(s):

Breast Cancer ◽

Endothelial Cell ◽

Advanced Breast Cancer ◽

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Locally Advanced Breast Cancer ◽

Locally Advanced ◽

Focal Adhesion Kinase Expression ◽

Tumor Endothelial Cell ◽

Kinase Expression

Download Full-text

Dysregulation of focal adhesion kinase upon Toxoplasma gondii infection facilitates parasite translocation across polarised primary brain endothelial cell monolayers

Cellular Microbiology ◽

10.1111/cmi.13048 ◽

2019 ◽

Vol 21 (9) ◽

Cited By ~ 2

Author(s):

Emily C. Ross ◽

Gabriela C. Olivera ◽

Antonio Barragan

Keyword(s):

Endothelial Cell ◽

Toxoplasma Gondii ◽

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Brain Endothelial Cell ◽

Cell Monolayers ◽

Toxoplasma Gondii Infection

Download Full-text

Tissue factor pathway inhibitor (TFPI) interferes with endothelial cell migration by inhibition of both the Erk pathway and focal adhesion proteins

Thrombosis and Haemostasis ◽

10.1160/th07-10-0623 ◽

2008 ◽

Vol 99 (03) ◽

pp. 576-585 ◽

Cited By ~ 19

Author(s):

Mathieu Provençal ◽

Marisol Michaud ◽

Édith Beaulieu ◽

David Ratel ◽

Georges-Étienne Rivard ◽

...

Keyword(s):

Endothelial Cells ◽

Cell Migration ◽

Endothelial Cell ◽

Tissue Factor ◽

Focal Adhesion ◽

Tissue Factor Pathway Inhibitor ◽

Endothelial Cell Migration ◽

Cell Functions ◽

Tissue Factor Pathway

SummaryTissue factor pathway inhibitor (TFPI) is a plasma Kunitz-type serine protease inhibitor that is mainly known for its inhibition of tissue factor-mediated coagulation. In addition to its anticoagulant properties, emerging data show that TFPI may also regulate endothelial cell functions via a non-haemostatic pathway. In this work we demonstrate that at concentrations within the physiological range,TFPI inhibits both endothelial cell migration and their differentiation into capillary-like structures in vitro. These effects were specific to endothelial cells since no inhibitory effect was observed on the migration of tumor (glio- blastoma) cells. Inhibition of endothelial cell migration was correlated with a concomitant loss in cell adhesion,suggesting an alteration of focal adhesion complex integrity. Accordingly,we observed thatTFPI inhibited the phosphorylation of focal adhesion kinase and paxillin,two key proteins involved in the scaffolding of these complexes, and that this effect was specific to endothelial cells. These results suggest that TFPI influences the angiogenic process via a non-haemostatic pathway, by downregulating the migratory mechanisms of endothelial cells.

Download Full-text