Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidants, generated by activated neutrophils, have been implicated in the pathophysiology of vascular disorders and lung injury; however, mechanisms of oxidant-mediated endothelial barrier dysfunction are unclear. Here, we have investigated the role of focal adhesion kinase (FAK) in regulating hydrogen peroxide (H(2)O(2))-mediated tyrosine phosphorylation of intercellular adhesion proteins and barrier function in endothelium. Treatment of bovine pulmonary artery endothelial cells (BPAECs) with H(2)O(2) increased tyrosine phosphorylation of FAK, paxillin, beta-catenin, and vascular endothelial (VE)-cadherin and decreased transendothelial electrical resistance (TER), an index of cell-cell adhesion and/or cell-matrix adhesion. To study the role of FAK in H(2)O(2)-induced TER changes, BPAECs were transfected with vector or FAK wild-type or FAK-related non-kinase (FRNK) plasmids. Overexpression of FRNK reduced FAK expression and attenuated H(2)O(2)-mediated tyrosine phosphorylation of FAK, paxillin, beta-catenin, and VE-cadherin and cell-cell adhesion. Additionally, FRNK prevented H(2)O(2)-induced distribution of FAK, paxillin, beta-catenin, or VE-cadherin toward focal adhesions and cell-cell adhesions but not actin stress fiber formation. These results suggest that activation of FAK by H(2)O(2) is an important event in oxidant-mediated VE barrier function regulated by cell-cell and cell-matrix contacts.
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PMID:Regulation of reactive oxygen species-induced endothelial cell-cell and cell-matrix contacts by focal adhesion kinase and adherens junction proteins. 1604 Jun 28

We cloned and characterized human WNT2B (WNT13) in 1996. Following our discovery of human WNT2B, others and we characterized mouse, rat, chicken and zebrafish WNT2B orthologs. Here, comparative integromics analyses on WNT2B and its clinical applications are reviewed. WNT2B-ST7L-CAPZA1 locus at human chromosome 1p13.2 and WNT2-ST7-CAPZA2 locus at human chromosome 7q31.2 are paralogous regions within the human genome. Two splicing variants occur from human WNT2B gene due to alternative promoters. WNT2B splicing variant 1 encodes secreted-type glycoprotein with WNT domain (WNT2B isoform 1), while WNT2B splicing variant 2 encodes transmembrane-type glycoprotein with WNT domain (WNT2B isoform 2). WNT2B splicing variant 2 is the evolutionarily conserved major transcript of human WNT2B gene. Mammalian WNT2B orthologs acquired the transmembrane domain and integrin-targeting RGD motif during vertebrate evolution. Human WNT2B isoform 2 and other vertebrate WNT2B orthologs are canonical WNTs to determine cell fate through the activation of beta-catenin/TCF signaling pathway and SNAIL/EMT signaling pathway. E box and CCAAT box are conserved within mammalian WNT2B promoters. WNT2B functions as the stem cell factor for neural or retinal progenitor cells during embryogenesis, and also for gastric cancer, esophageal cancer and skin basal cell carcinoma during carcinogenesis. Anti-WNT2B monoclonal antibody could be applied as selection marker of stem cells in the field of stem cell biology. Soluble WNT2B protein or small molecule WNT2B mimic compounds could be developed for stem cell expansion in the fields of tissue engineering and regenerative medicine. Anti-WNT2B monoclonal antibodies, WNT2B RNAi compounds, or small molecule WNT2B inhibitors could be developed as novel therapeutic agents for gastric cancer and esophageal cancer in the field of clinical oncology.
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PMID:WNT2B: comparative integromics and clinical applications (Review). 1627 93

Pancreatic cancer is characterized by its invasiveness, early metastasis, and the production of large amounts of extracellular matrix (ECM). We analyzed the influence of type I collagen and fibronectin on the regulation of cellular adhesion in pancreatic cancer cell lines to characterize the role of ECM proteins in the development of pancreatic cancer. We show that collagen type I is able to initiate a disruption of the E-cadherin adhesion complex in pancreatic carcinoma cells. This is due to the increased tyrosine phosphorylation of the complex protein beta-catenin, which correlates with collagen type I-dependent activation of the focal adhesion kinase and its association with the E-cadherin complex. The activation and recruitment of focal adhesion kinase to the E-cadherin complex depends on the interaction of type I collagen with beta1-containing integrins and an integrin-mediated activation of the cellular kinase Src. The disassembly of the E-cadherin adhesion complex correlates with the nuclear translocation of beta-catenin, which leads to an increasing expression of the beta-catenin-Lef/Tcf target genes, cyclin D1 and c-myc. In addition to that, cells grown on collagen type I show enhanced cell proliferation. We show that components of the ECM, produced by the tumor, contribute to invasiveness and metastasis by reducing E-cadherin-mediated cell-cell adhesion and enhance proliferation in pancreatic tumor cells.
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PMID:Collagen type I induces disruption of E-cadherin-mediated cell-cell contacts and promotes proliferation of pancreatic carcinoma cells. 1665 17

Protein tyrosine kinase 6 (PTK6) (also called Brk or Sik) is an intracellular tyrosine kinase that is expressed in breast cancer and normal epithelial linings. In adult mice, PTK6 expression is high in villus epithelial cells of the small intestine. To explore functions of PTK6, we disrupted the mouse Ptk6 gene. We detected longer villi, an expanded zone of PCNA expression, and increased bromodeoxyuridine incorporation in the PTK6-deficient small intestine. Although differentiation of major epithelial cell types occurred, there was a marked delay in expression of intestinal fatty acid binding protein, suggesting a role for PTK6 in enterocyte differentiation. However, fat absorption was comparable in wild-type and Ptk6-/- mice. It was previously shown that the serine threonine kinase Akt is a substrate of PTK6 and that PTK6-mediated phosphorylation of Akt on tyrosine resulted in inhibition of Akt activity. Consistent with these findings, we detected increased Akt activity and nuclear beta-catenin in intestines of PTK6-deficient mice and decreased nuclear localization of the Akt substrate FoxO1 in villus epithelial cells. PTK6 contributes to maintenance of tissue homeostasis through negative regulation of Akt in the small intestine and is associated with cell cycle exit and differentiation in normal intestinal epithelial cells.
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PMID:Protein tyrosine kinase 6 negatively regulates growth and promotes enterocyte differentiation in the small intestine. 1678 82

E-cadherin mainly mediated the epithelial cell-cell adhesion, and integrin signaling can modulate the signaling pathway of E-cadherin in the different levels. Up to now, however, it is still unclear that whether E-cadherin could interfere with cell-matrix interaction, a typical adhesion through integrins. In this study we investigated the effects of E-cadherin on cell-matrix adhesion and alpha5beta1 integrin expression in human breast carcinoma cells. It was found that either mRNA or protein level of alpha5 and beta1 subunits of integrin decreased in E-cad-231 compared with Mock-231. Furthermore, the promoter activity of alpha5 gene was inhibited in E-cad-231 compared with Mock-231. Consistently, phosphorylated focal adhesion kinase, a closer key downstream protein kinase of integrin signaling, were also down-regulated in E-cad-231. Furthermore, distribution of beta-catenin was observed and data showed beta-catenin was accumulated in the nucleus in Mock-231, while disappeared from the nucleus and mainly accumulated near the cell surface membrane in E-cad-231. LiCl, a molecule that can inhibit the GSK-3beta activity and down-regulate beta-catenin degradation, could inversely stimulate expression of alpha5 and beta1 integrin. Taken together, these results indicated that positive expression of E-cadherin inhibits the cell adhesion to extracellular matrix mediated by alpha5beta1 integrin signaling.
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PMID:Positive expression of E-cadherin suppresses cell adhesion to fibronectin via reduction of alpha5beta1 integrin in human breast carcinoma cells. 1682 Oct 70

The mechanisms regulating the size of the cerebral cortex are poorly understood. Here, we demonstrate that the Rap1 guanine nucleotide exchange factor, C3G (Grf2, Rapgef1), controls the size of the cerebral precursor population. Mice lacking C3G show overproliferation of the cortical neuroepithelium. C3G-deficient neuroepithelial cells accumulate nuclear beta-catenin and fail to exit the cell cycle in vivo. C3G mutant neural precursor cells fail to activate Rap1, exhibit activation of Akt/PKB, inhibition of the beta-catenin-degrading enzyme, Gsk3beta and accumulation of cytosolic and nuclear beta-catenin when exposed to growth factors, in vitro. Our results show that the size of the cortical neural precursor population is controlled by C3G-mediated inhibition of the Ras signalling pathway.
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PMID:C3G regulates the size of the cerebral cortex neural precursor population. 1685 99

4-Hydroxy-2-nonenal (4-HNE), one of the major biologically active aldehydes formed during inflammation and oxidative stress, has been implicated in a number of cardiovascular and pulmonary disorders. 4-HNE has been shown to increase vascular endothelial permeability; however, the underlying mechanisms are unclear. Hence, in the current study, we tested our hypothesis that 4-HNE-induced changes in cellular thiol redox status may contribute to modulation of cell signaling pathways that lead to endothelial barrier dysfunction. Exposure of bovine lung microvascular endothelial cells (BLMVECs) to 4-HNE induced reactive oxygen species generation, depleted intracellular glutathione, and altered cell-cell adhesion as measured by transendothelial electrical resistance. Pretreatment of BLM-VECs with thiol protectants, N-acetylcysteine and mercaptopropionyl glycine, attenuated 4-HNE-induced decrease in transendothelial electrical resistance, reactive oxygen species generation, Michael protein adduct formation, protein tyrosine phosphorylation, activation of ERK, JNK, and p38 MAPK, and actin cytoskeletal rearrangement. Treatment of BLMVECs with 4-HNE resulted in the redistribution of FAK, paxillin, VE-cadherin, beta-catenin, and ZO-1, and intercellular gap formation. Western blot analyses confirmed the formation of 4-HNE-derived Michael adducts with the focal adhesion and adherens junction proteins. Also, 4-HNE decreased tyrosine phosphorylation of FAK without affecting total cellular FAK contents, suggesting the modification of integrins, which are natural FAK receptors. 4-HNE caused a decrease in the surface integrin in a time-dependent manner without altering total alpha5 and beta3 integrins. These results, for the first time, revealed that 4-HNE in redox-dependent fashion affected endothelial cell permeability by modulating cell-cell adhesion through focal adhesion, adherens, and tight junction proteins as well as integrin signal transduction that may lead dramatic alteration in endothelial cell barrier dysfunction during heart infarction, brain stroke, and lung diseases.
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PMID:Redox regulation of 4-hydroxy-2-nonenal-mediated endothelial barrier dysfunction by focal adhesion, adherens, and tight junction proteins. 1698 27

Epithelial-mesenchymal transition (EMT) refers to critical events occasionally observed during tumor progression, including invasion and metastasis, by which cancer cells acquire a fibroblast-like phenotype. Since the stromal cell-derived factor-1 (SDF-1)/CXCR4 system can facilitate lymph node metastasis in oral squamous cell carcinoma (SCC), we have explored the possibility that this system might be involved in EMT. Oral SCC cells, B88 and HNt, which have functional CXCR4 and lymph node metastatic potential, were found to lose their epithelial cell morphology due to SDF-1. In this context, the downregulation of epithelial markers, cytokeratin, E-cadherin and beta-catenin, and the upregulation of mesenchymal marker, vimentin and snail were detected. Furthermore, upregulation of vimentin by treatment with SDF-1 was impaired by phosphatidylinositol 3 kinase (PI3K) inhibitor Wortmannin, but not by mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor U0126. In the type I collagen embedding culture, SDF-1-treated B88 cells formed protruding extensions, but the effect was impaired by treatment with Wortmannin. These results suggested that EMT induced by the SDF-1/CXCR4 system might be involved in the lymph node metastasis of oral SCCs via activation of PI3K-Akt/PKB pathway.
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PMID:Epithelial-mesenchymal transition induced by the stromal cell-derived factor-1/CXCR4 system in oral squamous cell carcinoma cells. 1701 44

Sublethal renal ischemia induces tubular epithelium damage and kidney dysfunction. Using NRK-52E rat proximal tubular epithelial cells, we have established an in vitro model, which includes oxygen and nutrients deprivation, to study the proximal epithelial cell response to ischemia. By means of this system, we demonstrate that confluent NRK-52E cells lose monolayer integrity and detach from collagen IV due to: (i) actin cytoskeleton reorganization; (ii) Rac1 and RhoA activity alterations; (iii) Adherens junctions (AJ) and Tight junctions (TJ) disruption, involving redistribution but not degradation of E-cadherin, beta-catenin and ZO-1; (iv) focal adhesion complexes (FAC) disassembly, entangled by mislocalization of paxillin and FAK dephosphorylation. Reactive oxygen species (ROS) are generated during the deprivation phase and rapidly balanced at recovery involving MnSOD induction, among others. The use of antioxidants (NAC) prevented FAC disassembly by blocking paxillin redistribution and FAK dephosphorylation, without abrogating AJ or TJ disruption. In spite of this, NAC did not show any protective effect on cell detachment. H(2)O(2), as a pro-oxidant treatment, supported the contribution of ROS in tubular epithelial cell-matrix but not cell-cell adhesion alterations. In conclusion, ROS-mediated FAC disassembly was not sufficient for the proximal epithelial cell shedding in response to sublethal ischemia, which also requires intercellular adhesion disruption.
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PMID:Requirements for proximal tubule epithelial cell detachment in response to ischemia: role of oxidative stress. 1702 98

Inhibition of the JAK2/STAT pathway has been implicated recently in cytoprotective mechanisms in both vascular smooth muscle cells and astrocytes. The advent of JAK2-specific inhibitors provides a practical tool for the study of this pathway in different cellular types. An interest in finding methods to improve endothelial cell (EC) resistance to injury led us to examine the effect of JAK2/STAT inhibition on EC protection. Furthermore, the signaling pathways involved in JAK2/STAT inhibition-related actions were examined. Our results reveal, for the first time, that blockade of JAK2 with the tyrosine kinase inhibitor AG490 strongly protects cultured EC against cell detachment-dependent death and serum deprivation and increases reseeding efficiency. Confirmation of the specificity of the effects of JAK2 inhibition was attained by finding protective effects on transfection with a dominant negative JAK2. Furthermore, AG490 blocked serum deprivation-induced phosphorylation of JAK2. In terms of mechanism, treatment with AG490 induces several relevant responses, both in monolayer and detached cells. These mechanisms include the following: 1) Increase and nuclear translocation of the active, dephosphorylated form of beta-catenin. In functional terms, this translocation is transcriptionally active, and its protective effect is further supported by the stimulation of EC cytoprotection by transfectionally induced excess of beta-catenin. 2) Increase of platelet endothelial cell adhesion molecule (PECAM)/CD31 levels. 3) Increase in total and phosphorylated AKT. 4) Increase in phosphorylated glycogen synthase kinase (GSK)3alpha/beta. The present findings imply potential practical applications of JAK2 inhibition on EC. These applications affect not only EC in the monolayer but also circulating detached cells and involve mechanistic interactions not previously described.
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PMID:Mechanisms of endothelial cell protection by blockade of the JAK2 pathway. 1703 97


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