Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of caveolae in stretch- versus flow-induced vascular responses was investigated using caveolin 1-deficient [knockout (KO)] mice. Portal veins were stretched longitudinally for 5 min (acute) or 72 h (organ culture). Basal ERK1/2 and Akt phosphorylation were increased in organ-cultured KO veins, as were protein synthesis and vessel wall cross sections. Stretch stimulated acute phosphorylation of ERK1/2 and long-term phosphorylation of focal adhesion kinase (FAK) and cofilin but did not affect Akt phosphorylation. Protein synthesis, and particularly synthesis of smooth muscle differentiation markers, was increased by stretch. These effects did not differ in portal veins from KO and control mice, which also showed the same contractile response to membrane depolarization and inhibition by the Rho kinase inhibitor Y-27632. KO carotid arteries had increased wall cross sections and responded to pressurization (120 mmHg) for 1 h with increased ERK1/2 but not Akt phosphorylation, similar to control arteries. Shear stress by flow for 15 min, on the other hand, increased phosphorylation of Akt in carotids from control but not KO mice. In conclusion, caveolin 1 contributes to low basal ERK1/2 and Akt activity and is required for Akt-dependent signals in response to shear stress (flow) but is not essential for trophic effects of stretch (pressure) in the vascular wall.
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PMID:Differential dependence of stretch and shear stress signaling on caveolin-1 in the vascular wall. 1798 9

Adhesion is a hallmark of haematological and solid cancer cells. All five classes of cell adhesion molecules (CAM) - integrins, cadherins, immunoglobulin-like CAMs, selectins and CD44s - are characteristically dysregulated in human cancer. Adhesion enables and promotes cancer-defining biological processes like growth, survival, migration, extravasation, homing, and metastasis. Furthermore, cell adhesion mediates drug resistance (CAM-DR) in multiple myeloma, malignant lymphoma, acute and chronic leukaemias, as well as in pancreatic cancer, neuroblastoma, small cell and non-small cell lung cancer, mesothelioma, colorectal carcinoma, and breast cancer. Cell adhesion protects from death by radiation, genotoxic chemotherapy, or targeted pathway inhibitors. Adhesion molecules are overexpressed on drug resistant cells (e.g. multiple myeloma or prostate cancer). Very recently, several cell adhesion mediated survival pathways have been elucidated, with key mediators being LFA-1, VLA-4, FAK, ILK, Src, PI3K, Akt, Ras, MEK, Erk, HMG-CoA reductase, Rho, Rho kinase, PKC, and NFkB. Because the surface and the intracellular targets are now known and because specific compounds are becoming increasingly available, first clinical trials regarding ANTI-ADHESION therapies are ongoing. However, in comparison to the comprehensive preclinical and clinical knowledge about CAMs, the number of drugs developed thusfar is quite low. ANTI-ADHESION strategies include targeting of surface antigens, inhibition of cell adhesion associated pathways, inhibition of CAM-DR, and targeted drug delivery. As ANTI-ADHESION is based on general characteristics of cancer cells independent of specific disease entities or treatment modalities, it may become a successful, low-toxic and broadly applicable concept in cancer treatment.
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PMID:ANTI-ADHESION evolves to a promising therapeutic concept in oncology. 1839 55

Schwannomas are Schwann cell tumors of the nervous system that occur spontaneously and in patients with neurofibromatosis 2 (NF2) and lack the tumor suppressor merlin. Merlin is known to bind paxillin, beta1 integrin and focal adhesion kinase, members of focal contacts, multi-protein complexes that mediate cell adhesion to the extracellular matrix. Moreover, merlin-deficient Schwannomas show pathological adhesion to the extracellular matrix making the characterization of focal contacts indispensable. Using our Schwannoma in vitro model of human primary Schwann and Schwannoma cells, we here show that Schwannoma cells display an increased number of mature and stable focal contacts. In addition to an involvement of RhoA signaling via the Rho kinase ROCK, Rac1 plays a significant role in the pathological adhesion of Schwannoma cells. The Rac1 guanine exchange factor- beta-Pix, localizes to focal contacts in human primary Schwannoma cells, and we show that part of the Rac1 activation, an effect of merlin-deficiency, occurs at the level of focal contacts in human primary Schwannoma cells. Our results help explaining the pathological adhesion of Schwannoma cells, further strengthen the importance of RhoGTPase signaling in Schwannoma development, and suggest that merlin's role in tumor suppression is linked to focal contacts.
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PMID:Altered adhesive structures and their relation to RhoGTPase activation in merlin-deficient Schwannoma. 1844 79

The mammalian growth plate is a dynamic structure rich in extracellular matrix (ECM). Interactions of growth plate chondrocytes with ECM proteins regulate cell behavior. In this study, we compared chondrocyte adhesion and spreading dynamics on fibronectin (FN) and bone sialoprotein (BSP). Chondrocyte adhesion and spreading were also compared with fibroblasts to analyze potential cell-type-specific effects. Chondrocyte adhesion to BSP is independent of posttranslational modifications but is dependent on the RGD sequence in BSP. Whereas chondrocytes and fibroblasts adhered at similar levels on FN and BSP, cells displayed more actin-dependent spread on FN despite a 16x molar excess of BSP adsorbed to plastic. To identify intracellular mediators responsible for this difference in spreading, we investigated focal adhesion kinase (FAK)-Src and Rho-Rho kinase (ROCK) signaling. Although activated FAK localized to the vertices of adhered chondrocytes, levels of FAK activation did not correlate with the extent of spreading. Furthermore, Src inhibition reduced chondrocyte spreading on both FN and BSP, suggesting that FAK-Src signaling is not responsible for less cell spreading on BSP. In contrast, inhibition of Rho and ROCK in chondrocytes increased cell spreading on BSP and membrane protrusiveness on FN but did not affect cell adhesion. In fibroblasts, Rho inhibition increased fibroblast spreading on BSP while ROCK inhibition changed membrane protrusiveness of FN and BSP. In summary, we identify a novel role for Rho-ROCK signaling in regulating chondrocyte spreading and demonstrate both cell- and matrix molecule-specific mechanisms controlling cell spreading.
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PMID:Rho-ROCK signaling differentially regulates chondrocyte spreading on fibronectin and bone sialoprotein. 1846 28

Invadopodia are actin-rich subcellular protrusions with associated proteases used by cancer cells to degrade extracellular matrix (ECM) [1]. Molecular components of invadopodia include branched actin-assembly proteins, membrane trafficking proteins, signaling proteins, and transmembrane proteinases [1]. Similar structures exist in nontransformed cells, such as osteoclasts and dendritic cells, but are generally called podosomes and are thought to be more involved in cell-matrix adhesion than invadopodia [2-4]. Despite intimate contact with their ECM substrates, it is unknown whether physical or chemical ECM signals regulate invadopodia function. Here, we report that ECM rigidity directly increases both the number and activity of invadopodia. Transduction of ECM-rigidity signals depends on the cellular contractile apparatus [5-7], given that inhibition of nonmuscle myosin II, myosin light chain kinase, and Rho kinase all abrogate invadopodia-associated ECM degradation. Whereas myosin IIA, IIB, and phosphorylated myosin light chain do not localize to invadopodia puncta, active phosphorylated forms of the mechanosensing proteins p130Cas (Cas) and focal adhesion kinase (FAK) are present in actively degrading invadopodia, and the levels of phospho-Cas and phospho-FAK in invadopodia are sensitive to myosin inhibitors. Overexpression of Cas or FAK further enhances invadopodia activity in cells plated on rigid polyacrylamide substrates. Thus, in invasive cells, ECM-rigidity signals lead to increased matrix-degrading activity at invadopodia, via a myosin II-FAK/Cas pathway. These data suggest a potential mechanism, via invadopodia, for the reported correlation of tissue density with cancer aggressiveness.
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PMID:Extracellular matrix rigidity promotes invadopodia activity. 1871 59

RhoA a small G-protein that has an established role in cell growth and in regulation of the actin cytoskeleton. Far less is known about whether RhoA can modulate cell fate. We previously reported that sustained RhoA activation induces cardiomyocyte apoptosis (Del Re, D. P., Miyamoto, S., and Brown, J. H. (2007) J. Biol. Chem. 282, 8069-8078). Here we demonstrate that less chronic RhoA activation affords a survival advantage, protecting cardiomyocytes from apoptotic insult induced by either hydrogen peroxide treatment or glucose deprivation. Under conditions where RhoA is protective, we observe Rho kinase-dependent cytoskeletal rearrangement and activation of focal adhesion kinase (FAK). Activation of endogenous cardiomyocyte FAK leads to its increased association with the p85 regulatory subunit of phosphatidylinositol-3-kinase (PI3K) and to concomitant activation of Akt. Treatment of isolated perfused hearts with sphingosine 1-phosphate recapitulates this response. The pathway by which RhoA mediates cardiomyocyte Akt activation is demonstrated to require Rho kinase, FAK and PI3K, but not Src, based on studies with pharmacological inhibitors (Y-27632, LY294002, PF271 and PP2) and inhibitory protein expression (FAK-related nonkinase). Inhibition of RhoA-mediated Akt activation at any of these steps, including inhibition of FAK, prevents RhoA from protecting cardiomyocytes against apoptotic insult. We further demonstrate that stretch of cardiomyocytes, which activates endogenous RhoA, induces the aforementioned signaling pathway, providing a physiologic context in which RhoA-mediated FAK phosphorylation can activate PI3K and Akt. We suggest that RhoA-mediated effects on the cardiomyocyte cytoskeleton provide a novel mechanism for protection from apoptosis.
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PMID:Focal adhesion kinase as a RhoA-activable signaling scaffold mediating Akt activation and cardiomyocyte protection. 1885 12

Indole-3-carbinol (I3C), a phytochemical derived from cruciferous vegetables such as broccoli and Brussels sprouts, has potent antiproliferative effects in human breast cancer cells and has been shown to decrease metastatic spread of tumors in experimental animals. Using chemotaxis and fluorescent-bead cell motility assays, we demonstrated that I3C significantly decreased the in vitro migration of MDA-MB-231 cells, a highly invasive breast cancer cell line. Immunofluorescence staining of the actin cytoskeleton revealed that concurrent with the loss of cell motility, I3C treatment significantly increased stress fiber formation. Furthermore, I3C induced the localization of the focal adhesion component vinculin and tyrosine-phosphorylated proteins to the cell periphery, which implicates an indole-dependent enhancement of focal adhesions within the outer boundary of the cells. Coimmunoprecipitation analysis of focal adhesion kinase demonstrated that I3C stimulated the dynamic formation of the focal adhesion protein complex without altering the total level of individual focal adhesion proteins. The RhoA-Rho kinase pathway is involved in stress fiber and focal adhesion formation, and I3C treatment stimulated Rho kinase enzymatic activity and cofilin phosphorylation, which is a downstream target of Rho kinase signaling, but did not increase the level of active GTP-bound RhoA. Exposure of MDA-MB-231 cells to the Rho kinase inhibitor Y-27632, or expression of dominant negative RhoA ablated the I3C induced formation of stress fibers and of peripheral focal adhesions. Expression of constitutively active RhoA mimicked the I3C effects on both processes. Taken together, our data demonstrate that I3C induces stress fibers and peripheral focal adhesions in a Rho kinase-dependent manner that leads to an inhibition of motility in human breast cancer cells.
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PMID:Indole-3-carbinol inhibits MDA-MB-231 breast cancer cell motility and induces stress fibers and focal adhesion formation by activation of Rho kinase activity. 1917 91

The adult, virgin mammary gland is a highly organized branched ductal network comprising two major cell types: myoepithelial and luminal epithelial cells. To study the role and mechanism of focal adhesion kinase (FAK)-mediated signaling in mammary gland development and differentiation, we used a conditional Fak-knockout mammary epithelial cell (MEC) transplantation model. Conditional Cre recombinase (Cre)-mediated Fak deletion in primary cultured MECs isolated from FAK(lox/lox)/Rosa26Cre-ERT2 donor mice caused loss of FAK in all mammary cells. Transplantation of Fak-knockout MECs in a cleared mammary fat pad of immune-deficient recipient mice resulted in development of new but dilated virgin ducts with a disrupted myoepithelial and luminal epithelial cell multilayer and aberrant ductal morphogenesis during pregnancy. In the absence of FAK, MECs spread poorly, showed enhanced Rho kinase (ROCK)-mediated cytoskeletal contractility, and failed to respond to receptor-mediated cytoskeletal remodeling. Likewise, FAK deficiency fully inhibited branching morphogenesis of mammary gland organoids in a ROCK-dependent manner. Altogether these data suggest a model in which FAK coordinates contractile forces in MECs to maintain the bilayered cellular organization of myoepithelial and luminal epithelial cells in ducts, thus allowing proper mammary gland development and function.
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PMID:Complete focal adhesion kinase deficiency in the mammary gland causes ductal dilation and aberrant branching morphogenesis through defects in Rho kinase-dependent cell contractility. 1958 5

Cell migration involves the cooperative reorganization of the actin and microtubule cytoskeletons, as well as the turnover of cell-substrate adhesions, under the control of Rho family GTPases. RhoA is activated at the leading edge of motile cells by unknown mechanisms to control actin stress fiber assembly, contractility, and focal adhesion dynamics. The microtubule-associated guanine nucleotide exchange factor (GEF)-H1 activates RhoA when released from microtubules to initiate a RhoA/Rho kinase/myosin light chain signaling pathway that regulates cellular contractility. However, the contributions of activated GEF-H1 to coordination of cytoskeletal dynamics during cell migration are unknown. We show that small interfering RNA-induced GEF-H1 depletion leads to decreased HeLa cell directional migration due to the loss of the Rho exchange activity of GEF-H1. Analysis of RhoA activity by using a live cell biosensor revealed that GEF-H1 controls localized activation of RhoA at the leading edge. The loss of GEF-H1 is associated with altered leading edge actin dynamics, as well as increased focal adhesion lifetimes. Tyrosine phosphorylation of focal adhesion kinase and paxillin at residues critical for the regulation of focal adhesion dynamics was diminished in the absence of GEF-H1/RhoA signaling. This study establishes GEF-H1 as a critical organizer of key structural and signaling components of cell migration through the localized regulation of RhoA activity at the cell leading edge.
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PMID:Guanine nucleotide exchange factor-H1 regulates cell migration via localized activation of RhoA at the leading edge. 1962 50

Tumor infiltrating neutrophil granulocytes do not only exhibit tumor eliminating functions but also promote tumor progression. We have recently shown that neutrophil granulocytes can serve as linking cells for the adhesion of MDA-MB-468 breast carcinoma cells to pulmonary endothelium. Neutrophil granulocytes but not MDA-MB-468 cells express beta(2)-integrins, the ligands of the intercellular adhesion molecule (ICAM)-1, whereas ICAM-1 is strongly expressed on MDA-MB-468 cells. Consequently, the herein presented study was performed to investigate if this interaction has also an influence on the migratory activity of the tumor cells and whether ICAM-1 signaling plays a role in this process, too. We found that the continuous release of interleukin-8 (IL-8) and GRO-alpha by MDA-MB-468 cells increases the migratory activity of neutrophil granulocytes and attracts these cells towards the tumor cells which enables direct cell-cell interactions. These interactions in turn increase the migratory activity of the tumor cells in an ICAM-1 clustering-dependent mechanism since transfection of the tumor cells with specific siRNA against ICAM-1 abolished the effect. Moreover, ICAM-1 cross-linking on tumor cells induces the phosphorylation of focal adhesion components such as focal adhesion kinase and paxillin via src kinase as well as the activation of the p38 MAPK pathway via Rho kinase in a time-dependent manner. Our results provide evidence that ICAM-1 is coupled to intracellular signaling pathways involved in tumor cell migration. Thus, neutrophil granulocytes can act as modulators of the metastatic capability of tumor cells by ligation of ICAM-1.
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PMID:Neutrophil granulocytes promote the migratory activity of MDA-MB-468 human breast carcinoma cells via ICAM-1. 1974 13


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