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)

Lipoxins (LXs) are endogenously produced anti-inflammatory agents that modulate leukocyte trafficking and stimulate nonphlogistic macrophage phagocytosis of apoptotic neutrophils, thereby promoting the resolution of inflammation. Previous data suggest a role for altered protein phosphorylation and cytoskeletal rearrangement in LX-stimulated phagocytosis but the exact mechanisms remain unclear. In this study we examine the effects of LXA4 on the protein phosphorylation pattern of THP-1 cells differentiated into a macrophage-like phenotype. THP-1 cells stimulated with LXA4 (1 nM) exhibit dephosphorylation of a 220-kDa protein. Using mass spectrometry, this protein was identified as MYH9, a nonmuscle myosin H chain II isoform A, which is involved in cytoskeleton rearrangement. THP-1 cells treated with LXA4 adopt a polarized morphology with activated Cdc42 localized toward the leading edge and MYH9 localized at the cell posterior. Polarized distribution of Cdc42 is associated with Akt/PKB-mediated Cdc42 activation. Interestingly, the annexin-derived peptide Ac2-26, a recently described agonist for the LXA4 receptor, also stimulates macrophage phagocytosis, MYH9 dephosphorylation, and MYH9 redistribution. In addition, we demonstrate that LXA4 stimulates the phosphorylation of key polarity organization molecules: Akt, protein kinase Czeta, and glycogen synthase kinase-3beta. Inhibition of LXA4-induced Akt and protein kinase Czeta activity with specific inhibitors prevented LXA4-stimulated phagocytosis of both apoptotic polymorphonuclear neutrophils and lymphocytes, highlighting a potential use for LXA4 in the treatment of autoimmune diseases. Furthermore, phosphorylation and subsequent inactivation of glycogen synthase kinase-3beta resulted in an increase in phagocytosis similar to that of LXA4. These data highlight an integrated mechanism whereby LXA4 regulates phagocytosis through facilitative actin cytoskeleton rearrangement and cell polarization.
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PMID:Lipoxin A4 redistributes myosin IIA and Cdc42 in macrophages: implications for phagocytosis of apoptotic leukocytes. 1642 19

Although two-dimensional cultures have been used extensively in cell biological research, most cells in vivo exist in a three-dimensional environment with complex topographical features, which may account for at least part of the striking differences between cells grown in vivo and in vitro. To investigate how substrate topography affects cell shape and movement, we plated fibroblasts on chemically identical polystyrene substrates with either flat surfaces or micron-sized pillars. Compared to cells on flat surfaces, 3T3 cells on pillar substrates showed a more branched shape, an increased linear speed, and a decreased directional stability. These responses may be attributed to stabilization of cell adhesion on pillars coupled to myosin II-dependent contractions toward pillars. Moreover, using FAK-/- fibroblasts we showed that focal adhesion kinase, or FAK, is essential for the responses to substrate topography. We propose that increased surface contact provided by topographic features guides cell migration by regulating the strength of local adhesions and contractions, through a FAK- and myosin II-dependent mechanism.
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PMID:Cellular responses to substrate topography: role of myosin II and focal adhesion kinase. 1650 Sep 65

Myosin II activation is essential for stress fiber and focal adhesion formation, and is implicated in integrin-mediated signaling events. In this study we investigated the role of acto-myosin contractility, and its main regulators, i.e. myosin light chain kinase (MLCK) and Rho-kinase (ROCK) in cell survival in normal and Ras-transformed MCF-10A epithelial cells. Treatment of cells with pharmacological inhibitors of MLCK (ML-7 and ML-9), or expression of dominant-negative MLCK, led to apoptosis in normal and transformed MCF-10A cells. By contrast, treatment of cells with a ROCK inhibitor (Y-27632) did not induce apoptosis in these cells. Apoptosis following inhibition of myosin II activation by MLCK is probably meditated through the death receptor pathway because expression of dominant-negative FADD blocked apoptosis. The apoptosis observed after MLCK inhibition is rescued by pre-treatment of cells with integrin-activating antibodies. In addition, this rescue of apoptosis is dependent on FAK activity, suggesting the participation of an integrin-dependent signaling pathway. These studies demonstrate a newly discovered role for MLCK in the generation of pro-survival signals in both untransformed and transformed epithelial cells and supports previous work suggesting distinct cellular roles for Rho-kinase- and MLCK-dependent regulation of myosin II.
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PMID:Myosin light chain kinase plays a role in the regulation of epithelial cell survival. 1672 33

Differentiation of stromal cells into decidual cells, which is critical to successful pregnancy, represents a complex transformation requiring changes in cytoskeletal architecture. We demonstrate that in vitro differentiation of human uterine fibroblasts into decidual cells includes down-regulation of alpha-smooth muscle actin and beta-tubulin, phosphorylation of focal adhesion kinase, and redistribution of vinculin. This is accompanied by varied adhesion to fibronectin and a modified ability to migrate. Cytoskeletal organization is determined primarily by actin-myosin II interactions governed by the phosphorylation of myosin light chain (MLC20). Decidualization induced by cAMP [with estradiol-17beta (E) and medroxyprogesterone acetate (P)] results in a 40% decrease in MLC20 phosphorylation and a 55% decline in the long (214 kDa) form of myosin light-chain kinase (MLCK). Destabilization of the cytoskeleton by inhibitors of MLCK (ML-7) or myosin II ATPase (blebbistatin) accelerates decidualization induced by cAMP (with E and P) but inhibits decidualization induced by IL-1beta (with E and P). Adenoviral infection of human uterine fibroblast cells with a constitutively active form of MLCK followed by decidualization stimuli leads to a 30% increase in MLC20 phosphorylation and prevents decidualization. These data provide evidence that the regulation of cytoskeletal dynamics by MLC20 phosphorylation is critical for decidualization.
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PMID:Increased phosphorylation of myosin light chain prevents in vitro decidualization. 1741 15

Eph receptors and ephrin ligands are widely expressed in epithelial cells and mediate cell repulsive motility through heterotypic cell-cell interactions. Several Ephs, including EphA2, are greatly overexpressed in certain tumors, in correlation with poor prognosis and high vascularity in cancer tissues. The ability of several Eph receptors to regulate cell migration and invasion likely contribute to tumor progression and metastasis. We report here that in prostatic carcinoma cells ephrinA1 elicits a repulsive response that is executed through a Rho-dependent actino/myosin contractility activation, ultimately leading to retraction of the cell body. This appears to occur through assembly of an EphA2-associated complex involving the two kinases Src and focal adhesion kinase (FAK). EphrinA1-mediated repulsion leads to the selective phosphorylation of Tyr-576/577 of FAK, enhancing FAK kinase activity. The repulsive response elicited by ephrinA1 in prostatic carcinoma cells is mainly driven by a Rho-mediated phosphorylation of myosin light chain II, in which Src and FAK activation are required steps. Consequently, Src and FAK are upstream regulators of the overall response induced by ephrinA1/EphA2, instructing cells to retract the cell body and to move away, probably facilitating dissemination and tissue invasion of ephrin-sensitive carcinomas.
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PMID:EphrinA1 activates a Src/focal adhesion kinase-mediated motility response leading to rho-dependent actino/myosin contractility. 1744 13

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

The cytoskeleton, integrin-mediated adhesion, and substrate stiffness control a common set of cell functions required for development and homeostasis that are often deranged in cancer. The connection between these mechanical elements and chemical signaling processes is not known. Here, we show that alpha(5)beta(1) integrin switches between relaxed and tensioned states in response to myosin II-generated cytoskeletal force. Force combines with extracellular matrix stiffness to generate tension that triggers the integrin switch. This switch directly controls the alpha(5)beta(1)-fibronectin bond strength through engaging the synergy site in fibronectin and is required to generate signals through phosphorylation of focal adhesion kinase. In the context of tissues, this integrin switch connects cytoskeleton and extracellular matrix mechanics to adhesion-dependent motility and signaling pathways.
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PMID:Mechanically activated integrin switch controls alpha5beta1 function. 1917 15

Repetitive strain stimulates intestinal epithelial migration across fibronectin via focal adhesion kinase (FAK), Src, and extracellular signal-related kinase (ERK) although how these signals act and interact remains unclear. We hypothesized that PI3K is central to this pathway. We subjected Caco-2 and intestinal epithelial cell-6 cells to 10 cycles/min deformation on flexible fibronectin-coated membranes, assayed migration by wound closure, and signaling by immunoblots. Strain stimulated PI3K, AKT, glycogen synthase kinase (GSK), and p38 phosphorylation. Blocking each kinase prevented strain stimulation of migration. Blocking PI3K prevented strain-stimulated ERK and p38 phosphorylation. Blocking AKT did not. Downstream, blocking PI3K, AKT, or ERK inhibited strain-induced GSK-Ser9 phosphorylation. Upstream of AKT, reducing FAK or Rac1 by siRNA blocked strain-stimulated AKT phosphorylation, but inhibiting Src by PP2 or siRNA did not. Transfection with FAK point mutants at Tyr397, Tyr576/577, or Tyr925 demonstrated that only FAK925 phosphorylation is required for strain-stimulated AKT phosphorylation. Myosin light chain activation by strain required FAK, Rac1, PI3K, AKT, GSK, and ERK but not Src or p38. Finally, blebbistatin, a nonmuscle myosin II inhibitor, blocked the motogenic effect of strain downstream of myosin light chain. Thus strain stimulates intestinal epithelial migration across fibronectin by a complex pathway including Src, FAK, Rac1, PI3K, AKT, GSK, ERK, p38, myosin light chain, and myosin II.
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PMID:Delineating the signals by which repetitive deformation stimulates intestinal epithelial migration across fibronectin. 1917 20

Long-term clinical outcomes are dependent on whether carcinoma cells leave the primary tumor site and invade through adjacent tissue. Recent evidence links tissue rigidity to alterations in cancer cell phenotype and tumor progression. We found that rigid extracellular matrix (ECM) substrates promote invasiveness of tumor cells via increased activity of invadopodia, subcellular protrusions with associated ECM-degrading proteinases. Although the subcellular mechanism by which substrate rigidity promotes invadopodia function remains to be determined, force sensing does appear to occur through myosin-based contractility and the mechanosensing proteins FAK and p130(Cas). In addition to rigidity, a number of ECM characteristics may regulate the ability of cells to invade through tissues, including matrix density and crosslinking. 3-D biological hydrogels based on type I collagen and reconstituted basement membrane are commonly used to study invasive behavior; however, these models lack some of the tissue-specific properties found in vivo. Thus, new in vitro organotypic and synthetic polymer ECM substrate models will be useful to either mimic the properties of specific ECM microenvironments encountered by invading cancer cells or to manipulate ECM substrate properties and independently test the role of rigidity, integrin ligands, pore size and proteolytic activity in cancer invasion of various tissues.
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PMID:Regulation of cancer invasiveness by the physical extracellular matrix environment. 1945 99

Cells within tissues derive mechanical anchorage and specific molecular signals from the insoluble extracellular matrix (ECM) that surrounds them. Understanding the role of different cues that extracellular matrices provide cells is critical for controlling and predicting cell response to scaffolding materials. Using an engineered extracellular matrix of Type I collagen we examined how the stiffness, supramolecular structure, and glycosylation of collagen matrices influence the protein levels of cellular FAK and the activation of myosin II. Our results show that (1) cellular FAK is downregulated on collagen fibrils, but not on a non-fibrillar monolayer of collagen, (2) the downregulation of FAK is independent of the stiffness of the collagen fibrils, and (3) FAK levels are correlated with levels of tyrosine phosphorylation of the collagen adhesion receptor DDR2. Further, siRNA depletion of DDR2 blocks FAK downregulation. Our results suggest that the collagen receptor DDR2 is involved in the regulation of FAK levels in vSMC adhered to Type I collagen matrices, and that regulation of FAK levels in these cells appears to be independent of matrix stiffness.
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PMID:The relative roles of collagen adhesive receptor DDR2 activation and matrix stiffness on the downregulation of focal adhesion kinase in vascular smooth muscle cells. 1976 78


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