Protein tyrosine phosphatase-dependent proteolysis of focal adhesion complexes in endothelial cell apoptosis

2001 ◽  
Vol 280 (2) ◽  
pp. L342-L353 ◽  
Author(s):  
Elizabeth O. Harrington ◽  
Anthony Smeglin ◽  
Julie Newton ◽  
Gajarah Ballard ◽  
Sharon Rounds
Keyword(s):  
Endothelial Cell ◽  
Focal Adhesion ◽  
Protein Tyrosine Phosphatase ◽  
Cell Apoptosis ◽  
Tyrosine Phosphatase ◽  
Sodium Orthovanadate ◽  
Endothelial Cell Apoptosis ◽  
Protein Tyrosine ◽  
Adhesion Contact ◽  
Endothelial Cell Retraction

Adenosine and/or homocysteine causes endothelial cell apoptosis, a mechanism requiring protein tyrosine phosphatase (PTPase) activity. We investigated the role of focal adhesion contact disruption in adenosine-homocysteine endothelial cell apoptosis. Analysis of focal adhesion kinase (FAK), paxillin, and vinculin demonstrated disruption of focal adhesion complexes after 4 h of treatment with adenosine-homocysteine followed by caspase-induced proteolysis of FAK, paxillin, and p130CAS. No significant changes were noted in tyrosine phosphorylation of FAK or paxillin. Pretreatment with the caspase inhibitor Z-Val-Ala-Asp-fluoromethylketone prevented adenosine-homocysteine-induced DNA fragmentation and FAK, paxillin, and p130CAS proteolysis. Asp-Glu-Val-Asp-ase activity was detectable in endothelial cells after 4 h of treatment with adenosine-homocysteine. The PTPase inhibitor sodium orthovanadate did not prevent endothelial cell retraction or FAK, paxillin, or vinculin redistribution. Sodium orthovanadate did block adenosine-homocysteine-induced FAK, paxillin, and p130CASproteolysis and Asp-Glu-Val-Asp-ase activity. Thus disruption of focal adhesion contacts and caspase-induced degradation of focal adhesion contact proteins occurs in adenosine-homocysteine endothelial cell apoptosis. Focal adhesion contact disruption induced by adenosine-homocysteine is independent of PTPase or caspase activation. These studies demonstrate that disruption of focal adhesion contacts is an early, but not an irrevocable, event in endothelial cell apoptosis.

scholarly journals Focal adhesion kinase regulates the phosphorylation protein tyrosine phosphatase-α at Tyr789 in breast cancer cells

2015 ◽  
Vol 11 (6) ◽  
pp. 4303-4308 ◽  
Author(s):  
XU-QIAN FANG ◽  
XIANG-FAN LIU ◽  
LING YAO ◽  
CHANG-QIANG CHEN ◽  
JIA-FEI LIN ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Focal Adhesion Kinase ◽  
Cancer Cells ◽  
Focal Adhesion ◽  
Protein Tyrosine Phosphatase ◽  
Breast Cancer Cells ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine

scholarly journals Protein-tyrosine Phosphatase Shp-2 Regulates Cell Spreading, Migration, and Focal Adhesion

1998 ◽  
Vol 273 (33) ◽  
pp. 21125-21131 ◽  
Author(s):  
De-Hua Yu ◽  
Cheng-Kui Qu ◽  
Octavian Henegariu ◽  
Xiaolan Lu ◽  
Gen-Sheng Feng
Keyword(s):  
Focal Adhesion ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Cell Spreading ◽  
Protein Tyrosine

scholarly journals New Role for the Protein Tyrosine Phosphatase DEP-1 in Akt Activation and Endothelial Cell Survival

2008 ◽  
Vol 29 (1) ◽  
pp. 241-253 ◽  
Author(s):  
Catherine Chabot ◽  
Kathleen Spring ◽  
Jean-Philippe Gratton ◽  
Mounib Elchebly ◽  
Isabelle Royal
Keyword(s):  
Endothelial Cell ◽  
Cell Survival ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Growth Factor Receptor ◽  
Endothelial Cell Proliferation ◽  
Protein Tyrosine ◽  
Akt Activation ◽  
Endothelial Cell Survival ◽  
Functional Inactivation

ABSTRACT Functional inactivation of the protein tyrosine phosphatase DEP-1 leads to increased endothelial cell proliferation and failure of vessels to remodel and branch. DEP-1 has also been proposed to contribute to the contact inhibition of endothelial cell growth via dephosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2), a mediator of vascular development. However, how DEP-1 regulates VEGF-dependent signaling and biological responses remains ill-defined. We show here that DEP-1 targets tyrosine residues in the VEGFR2 kinase activation loop. Consequently, depletion of DEP-1 results in the increased phosphorylation of all major VEGFR2 autophosphorylation sites, but surprisingly, not in the overall stimulation of VEGF-dependent signaling. The increased phosphorylation of Src on Y529 under these conditions results in impaired Src and Akt activation. This inhibition is similarly observed upon expression of catalytically inactive DEP-1, and coexpression of an active Src-Y529F mutant rescues Akt activation. Reduced Src activity correlates with decreased phosphorylation of Gab1, an adapter protein involved in VEGF-dependent Akt activation. Hypophosphorylated Gab1 is unable to fully associate with phosphatidylinositol 3-kinase, VEGFR2, and VE-cadherin complexes, leading to suboptimal Akt activation and increased cell death. Overall, our results reveal that despite its negative role on global VEGFR2 phosphorylation, DEP-1 is a positive regulator of VEGF-mediated Src and Akt activation and endothelial cell survival.

scholarly journals Protein Tyrosine Phosphatase-PEST Regulates Focal Adhesion Disassembly, Migration, and Cytokinesis in Fibroblasts

1999 ◽  
Vol 144 (5) ◽  
pp. 1019-1031 ◽  
Author(s):  
Alexandre Angers-Loustau ◽  
Jean-François Côté ◽  
Alain Charest ◽  
Donald Dowbenko ◽  
Susan Spencer ◽  
...  
Keyword(s):  
Tyrosine Phosphorylation ◽  
Focal Adhesion ◽  
Protein Tyrosine Phosphatase ◽  
Matrix Protein ◽  
Tyrosine Phosphatase ◽  
Control Cell ◽  
Focal Adhesions ◽  
Extracellular Matrix Protein ◽  
Cleavage Furrow ◽  
Protein Tyrosine

In this article, we show that, in transfected COS-1 cells, protein tyrosine phosphatase (PTP)-PEST translocates to the membrane periphery following stimulation by the extracellular matrix protein fibronectin. When plated on fibronectin, PTP-PEST (−/−) fibroblasts display a strong defect in motility. 3 h after plating on fibronectin, the number and size of vinculin containing focal adhesions were greatly increased in the homozygous PTP-PEST mutant cells as compared with heterozygous cells. This phenomenon appears to be due in part to a constitutive increase in tyrosine phosphorylation of p130CAS, a known PTP-PEST substrate, paxillin, which associates with PTP-PEST in vitro, and focal adhesion kinase (FAK). Another effect of this constitutive hyperphosphorylation, consistent with the focal adhesion regulation defect, is that (−/−) cells spread faster than the control cell line when plated on fibronectin. In the PTP-PEST (−/−) cells, an increase in affinity for the SH2 domains of Src and Crk towards p130CAS was also observed. In (−/−) cells, we found a significant increase in the level of tyrosine phosphorylation of PSTPIP, a cleavage furrow–associated protein that interacts physically with all PEST family members. An effect of PSTPIP hyperphosphorylation appears to be that some cells remain attached at the site of the cleavage furrow for an extended period of time. In conclusion, our data suggest PTP-PEST plays a dual role in cell cytoskeleton organization, by promoting the turnover of focal adhesions required for cell migration, and by directly or indirectly regulating the proline, serine, threonine phosphatase interacting protein (PSTPIP) tyrosine phosphorylation level which may be involved in regulating cleavage furrow formation or disassembly during normal cell division.

scholarly journals Protein tyrosine phosphatase 1B, PTP1B, targets fak and paxillin in cell-matrix adhesions

2021 ◽  
Author(s):  
Ana E. González Wusener ◽  
Ángela González ◽  
María E. Perez Collado ◽  
Melina R. Maza ◽  
Ignacio J. General ◽  
...  
Keyword(s):  
Focal Adhesion ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Bimolecular Fluorescence Complementation ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine ◽  
Matrix Adhesion ◽  
Cell Matrix ◽  
Adhesion Sites ◽  
Cell Matrix Adhesion

Protein tyrosine phosphatase 1B (PTP1B) is an established regulator of cell-matrix adhesion and motility. However, the nature of substrate targets at adhesion sites remains to be validated. Here we used Bimolecular Fluorescence Complementation (BiFC) assays in combination with a substrate trapping mutant of PTP1B to directly examine whether relevant phosphotyrosines on paxillin and FAK are substrates of the phosphatase in the context of cell-matrix adhesion sites. We find that formation of catalytic complexes at cell-matrix adhesions requires intact tyrosine residues Y31 and Y118 on paxillin and the localization of the focal adhesion kinase (FAK) at adhesion sites. In addition, we find that PTP1B specifically targets the Y925 on the focal adhesion target (FAT) domain of FAK at adhesion sites. Electrostatic analysis indicates that dephosphorylation of this residue promotes the closed conformation of the FAT 4-helix bundle, and its interaction with paxillin at adhesion sites.

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