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)

Our previous studies demonstrated that the proinflammatory peptide, macrophage migration inhibitory factor (MIF), functions as an autocrine mediator of both growth factor- and integrin-dependent sustained ERK MAPK activation, cyclin D1 expression, and cell cycle progression. We now report that MIF promotes the activation of the canonical ERK MAPK cascade and cyclin D1 expression by stimulating the activity of the Rho GTPase and downstream signaling to stress fiber formation. Rho-dependent stress fiber accumulation promotes the sustained activation of ERK and subsequent cyclin D1 expression during G(1)-S phase cell cycle progression. This pathway is reported to be dependent upon myosin light chain (MLC) kinase, integrin clustering, and subsequent activation of focal adhesion kinase, leading to sustained MAPK activity. Our studies reveal that recombinant MIF induces cyclin D1 expression in a Rho-, Rho kinase-, MLC kinase-, and ERK-dependent manner in asynchronous NIH 3T3 fibroblasts. Moreover, MIF(-/-) murine embryonic fibroblasts display aberrant cyclin D1 expression that is linked to defective Rho activity, stress fiber formation, and MLC phosphorylation. These results suggest that MIF is an integral autocrine mediator of Rho GTPase-dependent signaling events and provide mechanistic insight into how MIF regulates proliferative, migratory, and oncogenic processes.
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PMID:Rho GTPase-dependent signaling is required for macrophage migration inhibitory factor-mediated expression of cyclin D1. 1584 May 82

Protease-activated receptors (PARs) activate Gq and G(12/13) pathways, as well as Akt (protein kinase B [PKB/Akt]) in platelets. However, the relative contribution of different G-protein pathways to Akt phosphorylation has not been elucidated. We investigated the contribution of Gq and G(12/13) to Gi/Gz-mediated Akt phosphorylation downstream of PAR activation. Selective G(12/13) activation failed to cause Akt phosphorylation in human and Galpha q-deficient mouse platelets. However, supplementing Gi/Gz signaling to G(12/13) caused significant increase in Akt phosphorylation, confirming that G(12/13) potentiates Akt phosphorylation. Inhibition of PAR-mediated Akt phosphorylation in the presence of the Gq-selective inhibitor YM-254890 was restored to the normal extent achieved by PAR agonists if supplemented with Gi signaling, indicating that Gq does not have any direct effect on Akt phosphorylation. Selective G(12/13) activation resulted in Src kinase activation, and Akt phosphorylation induced by costimulation of G(12/13) and Gi/Gz was inhibited by a Src kinase inhibitor but not by a Rho kinase inhibitor. These data demonstrate that G(12/13), but not Gq, is essential for thrombin-induced Akt phosphorylation in platelets, whereas Gq indirectly contributes to Akt phosphorylation through Gi stimulation by secreted ADP. G(12/13) activation might mediate its potentiating effect through Src activation, and Src kinases play an important role in thrombin-mediated Akt phosphorylation.
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PMID:Relative contribution of G-protein-coupled pathways to protease-activated receptor-mediated Akt phosphorylation in platelets. 1622 79

The membrane redistribution and phosphorylation of focal adhesion kinase (FAK) have been reported to be important for cell migration. We previously showed that Lysophosphatidic acid (LPA) induced FAK membrane redistribution and autophosphorylation in ovarian cancer SK-OV3 cells and the signaling pathway consisting of Gi-Ras-MEKK1 mediated LPA-induced FAK membrane redistribution but not FAK autophosphorylation. We also showed that the disruption of the Gi-Ras-MEKK1 pathway led to a significant reduction in LPA-stimulated cell migration. These findings raised the question of whether LPA-induced FAK autophosphorylation was required for LPA-stimulated cell migration and what signaling mechanism was involved in LPA-induced FAK autophosphorylation. In this study, we expressed the membrane anchored wild-type FAK (CD2-FAK) in SK-OV3 cells and found that the expression of CD2-FAK greatly rescued LPA-stimulated cell migration in Gi or Ras-inhibited cells. However, Gi inhibitor pertussis toxin or dominant-negative H-Ras still significantly inhibited LPA-stimulated cell migration in cells expressing the membrane anchored FAK containing a mutation in the autophosphorylation site [CD2-FAK(Y397A)]. These results suggest that FAK autophosphorylation plays a role in LPA-stimulated cell migration. With the aid of p115RhoGEF-RGS, G12 and G13 minigenes to inhibit G12/13, we found that the G12/13 pathway was required for LPA-induced FAK autophosphorylation and efficient cell migration. Moreover, LPA activated RhoA and Rho kinase (ROCK) in a G12/13-dependent manner and their activities were required for LPA-induced FAK autophosphorylation. However, Rho or ROCK inhibitors displayed no effect on LPA-induced FAK membrane redistribution although they abolished LPA-induced cytoskeleton reorganization. Our studies show that the G12/13-RhoA-ROCK signaling pathway mediates LPA-induced FAK autophosphorylation and contributes to LPA-stimulated cell migration.
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PMID:The G12/13-RhoA signaling pathway contributes to efficient lysophosphatidic acid-stimulated cell migration. 1630 93

Lipoma preferred partner (LPP) has been identified as a protein highly expressed in smooth muscle (SM) tissues. The aim of the present study was to determine mechanisms that regulate LPP expression in an in vitro model of SM cell (SMC) differentiation and in stent-induced pig coronary vessel injury. All trans-retinoic acid treatment of A404 cells induced a strong increase in LPP, as well as SM alpha-actin, SM myosin heavy chain, and smoothelin mRNA levels, in a Rho kinase (ROK)-dependent manner. Adenovirus mediated overexpression of myocardin in A404 cells significantly increased LPP mRNA expression. Interestingly, inactivation of RhoA with C3-exoenzyme or treatment with ROK inhibitors strongly inhibited myocardin mRNA expression in retinoic acid-treated A404 cells or human iliac vein SMCs. LPP silencing with short interfering RNA significantly decreased SMC migration. LPP expression was also markedly decreased in focal adhesion kinase (FAK)-null cells known to have impaired migration but rescued with inducible expression of FAK. LPP expression in FAK-null fibroblasts enhanced cell spreading. In stented pig coronary vessels, LPP was expressed in the neointima of cells lacking smoothelin and showed expression patterns identical to those of SM alpha-actin. In conclusion, LPP appears to be a myocardin-, RhoA/ROK-dependent SMC differentiation marker that plays a role in regulating SMC migration.
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PMID:LPP expression during in vitro smooth muscle differentiation and stent-induced vascular injury. 1648 26

The calcium-dependent proline-rich tyrosine kinase Pyk2 is activated by tyrosine phosphorylation, associates with focal adhesion proteins, and has been linked to proliferative and migratory responses in a variety of mesenchymal and epithelial cell types. Full Pyk2 activation requires phosphorylation at functionally distinct sites, including autophosphorylation site Tyr-402 and catalytic domain site Tyr-580, though the mechanisms involved are unclear. The pathways mediating Pyk2 phosphorylation at Tyr-402 and Tyr-580 were therefore investigated. Both sites were rapidly and transiently phosphorylated following cell stimulation by Ang II or LPA. However, only Tyr-580 phosphorylation was rapidly enhanced by intracellular Ca(2+) release, or inhibited by Ca(2+) depletion. Conversely, Tyr-402 phosphorylation was highly sensitive to inhibition of actin stress fibers, or of Rho kinase (ROK), an upstream regulator of stress fiber assembly. Ang II also induced a delayed (30-60 min) secondary phosphorylation peak occurring at Tyr-402 alone. Unlike the homologous focal adhesion kinase (FAK), Pyk2 phosphorylation was sensitive neither to the Src inhibitor PP2, nor to truncation of its N-terminal region, which contains a putative autoinhibitory FERM domain. These results better define the mechanisms involved in Pyk2 activation, demonstrating that autophosphorylation is ROK- and stress fiber-dependent, while transphosphorylation within the kinase domain is Ca(2+)-dependent and Src-independent in intestinal epithelial cells. This contrasts with the tight sequential coupling of phosphorylation seen in FAK activation, and further underlines the differences between these closely related kinases.
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PMID:Differential regulation of Pyk2 phosphorylation at Tyr-402 and Tyr-580 in intestinal epithelial cells: roles of calcium, Src, Rho kinase, and the cytoskeleton. 1657 77

The ease of isolation and ex vivo culture of marrow-derived stromal cells (MSCs) from adult bone marrow renders them a very promising source of adult stem cells for gene transfer and cell therapy. However, little is known about the signaling pathways that control their in vivo mobilization and subsequent biodistribution. Platelet-derived sphingosine-1-phosphate (S1P), a bioactive lipid that acts via G-protein-coupled-receptors, exerts strong chemoattraction upon MSCs through yet-uncharacterized signaling pathways. We show that the S1P-induced migration and morphological changes of MSCs in vitro require the activities of extracellular signal-regulated kinase (ERK), Rho kinase (ROCK), and matrix metalloproteinase (MMP) signaling molecules. Specifically, S1P-induced remodeling of the MSC cytoskeleton led to the rapid (<1 minute) formation of actin stress fibers via activation of the RhoA/ROCK pathway and required the catalytic activity of MMPs. S1P-induced activation of the mitogen-activated protein kinase kinase-1 (MEK1)/ERK pathway also contributed to the induction of the actin stress fibers and to the redistribution of paxillin at the focal adhesions through tyrosine phosphorylation of focal adhesion kinase in an MMP-dependent manner. Moreover, MMP- and ROCK-dependent molecular events are implicated in the regulation of the S1P-induced activation of ERK. Our results demonstrate that MSC mobilization in response to S1P requires cooperation between MMP-mediated signaling events and the RhoA/ROCK and MEK1/ERK intracellular pathways. Therefore, the characterization of the cellular factors and the intracellular signaling pathways underlying MSC mobilization is crucial to achieve high efficacy in therapeutic use.
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PMID:Cooperation of matrix metalloproteinases with the RhoA/Rho kinase and mitogen-activated protein kinase kinase-1/extracellular signal-regulated kinase signaling pathways is required for the sphingosine-1-phosphate-induced mobilization of marrow-derived stromal cells. 1693 73

Stimulation of PPARgamma1 and adipogenesis in multipotential C3H10T1/2 cells by the combination of dexamethasone and 3-isobutyl-1-methylxanthine (DM) is suppressed by 2,3,7,8 tetrachlorodibenzodioxin (TCDD) (10 nM). This suppression requires sustained activation of extracellular signal-regulated kinase (Erk)1/2. We show that it arises from an effect of TCDD on epidermal growth factor (EGF) signaling. DM initiates an early loss of cell adhesion that is reversed by this TCDD/EGF synergy. Src kinase activity was completely essential for adhesion restoration, sustained Erk activation, and suppression of peroxisome proliferator-activated receptor (PPAR)gamma1. MEK/Erk activity did not contribute, however, to TCDD-induced adhesion. Stimulation of adhesion may therefore precede elevation of Erk. Adhesion is produced by interaction of alphabeta integrins with extracellular matrix proteins and subsequent Src-mediated phosphorylation of focal adhesion kinase (FAK, Tyr576/577) and paxillin (Tyr118). TCDD enhanced the steady state Src-mediated phosphorylation of FAK but not of paxillin. Protein tyrosine phosphatase (PTPase) inhibition by orthovanadate (OVA) showed that this Src activity is highly restricted by PTPases. Partial inhibition of PTPases by OVA mimicked TCDD in producing EGF- and Src-dependent effects on cell adhesion and PPARgamma1 suppression. TCDD may therefore induce a protein that enhances Src effectiveness at adhesion sites. Rho kinase (ROCK) inhibition blocked TCDD/EGF stimulation of clustered focal adhesion complexes without affecting either sustained Erk activation or suppression of PPARgamma1. Thus, this ROCK-mediated clustering of integrin complexes is not needed for the effects of TCDD on Erk and PPARgamma1. A minimal cholesterol depletion with beta-methylcyclodextrin attenuated TCDD effects on PPARgamma1 and Erk activation. TCDD intervention is therefore linked to extracellular proteins. It indicates that TCDD-enhanced stimulation of EGF signaling to Erk may derive from the initial alphabeta integrin complexes.
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PMID:2,3,7,8-tetrachlorodibenzo-p-dioxin and epidermal growth factor cooperatively suppress peroxisome proliferator-activated receptor-gamma1 stimulation and restore focal adhesion complexes during adipogenesis: selective contributions of Src, Rho, and Erk distinguish these overlapping processes in C3H10T1/2 cells. 1697 54

Increased tissue or serum levels of oxidized phospholipids have been detected in a variety of chronic and acute pathological conditions such as hyperlipidemia, atherosclerosis, heart attack, cell apoptosis, acute inflammation and injury. We have recently described signaling cascades activated by oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC)in the human pulmonary artery endothelial cells (EC) and reported potent barrier-protective effects of OxPAPC, which were mediated by small GTPases Rac and Cdc42. In this study we have further characterized signal transduction pathways involved in the OxPAPC-mediated endothelial barrier protection. Inhibitors of small GTPases, protein kinase A (PKA), protein kinase C (PKC), Src family kinases and general inhibitors of tyrosine kinases attenuated OxPAPC-induced barrier-protective response and EC cytoskeletal remodeling. In contrast, small GTPase Rho, Rho kinase, Erk-1,2 MAP kinase and p38 MAP kinase and PI3-kinase were not involved in the barrier-protective effects of OxPAPC. Inhibitors of PKA, PKC, tyrosine kinases and small GTPase inhibitor toxin B suppressed OxPAPC-induced Rac activation and decreased phosphorylation of focal adhesion kinase (FAK) and paxillin. Barrier-protective effects of OxPAPC were not reproduced by platelet activating factor (PAF), which at high concentrations induced barrier dysfunction, but were partially attenuated by PAF receptor antagonist A85783. These results demonstrate for the first time upstream signaling cascades involved in the OxPAPC-induced Rac activation, cytoskeletal remodeling and barrier regulation and suggest PAF receptor-independent mechanisms of OxPAPC-mediated endothelial barrier protection.
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PMID:Signaling pathways involved in OxPAPC-induced pulmonary endothelial barrier protection. 1729 25

Exposure to an acid load increases apical membrane Na(+)/H(+) antiporter (NHE3) activity, a process that involves exocytic trafficking of the transporter to the apical membrane. We have previously shown that an intact microfilament structure is required for this exocytic process (Yang X, Amemiya M, Peng Y, Moe OW, Preisig PA, Alpern RJ. Am J Physiol Cell Physiol 279: C410-C419, 2000). The present studies demonstrate that acid-induced stress fiber formation is required for stimulation of NHE3 activity. Formation of stress fibers is associated with acid-induced tyrosine phosphorylation and increases in protein abundance of two focal adhesion proteins, p125(FAK) and paxillin. The Rho kinase inhibitor Y27632 completely blocks acid-induced stress fiber formation and the increases in apical membrane NHE3 abundance and activity, but it has no effect on acid-induced tyrosine phosphorylation of p125(FAK) or paxillin. Herbimycin A completely blocks acid-induced tyrosine phosphorylation of p125(FAK) and paxillin but only partially blocks stress fiber formation and NHE3 activation. These studies demonstrate that Rho kinase mediates acid-induced stress fiber formation, which is required for NHE3 exocytosis, and increases in NHE3 activity. Acid-induced tyrosine phosphorylation of the focal adhesion proteins p125(FAK) and paxillin is not Rho kinase dependent. Thus these two acid-mediated effects are associated, yet independent processes.
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PMID:RhoA required for acid-induced stress fiber formation and trafficking and activation of NHE3. 1768 51

Hyperosmotic shrinkage induces multiple cellular responses, including activation of volume-regulatory ion transport, cytoskeletal reorganization, and cell death. Here we investigated the possible roles of ezrin/radixin/moesin (ERM) proteins in these events. Osmotic shrinkage of Ehrlich Lettre ascites cells elicited the formation of long microvillus-like protrusions, rapid translocation of endogenous ERM proteins and green fluorescent protein-tagged ezrin to the cortical region including these protrusions, and Thr(567/564/558) (ezrin/radixin/moesin) phosphorylation of cortical ERM proteins. Reduced cell volume appeared to be the critical parameter in hypertonicity-induced ERM protein activation, whereas alterations in extracellular ionic strength or intracellular pH were not involved. A shrinkage-induced increase in the level of membrane-associated phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P(2)] appeared to play an important role in ERM protein activation, which was prevented after PtdIns(4,5)P(2) depletion by expression of the synaptojanin-2 phosphatase domain. While expression of constitutively active RhoA increased basal ERM phosphorylation, the Rho-Rho kinase pathway did not appear to be involved in shrinkage-induced ERM protein phosphorylation, which was also unaffected by the inhibition or absence of Na(+)/H(+) exchanger isoform (NHE1). Ezrin knockdown by small interfering RNA increased shrinkage-induced NHE1 activity, reduced basal and shrinkage-induced Rho activity, and attenuated the shrinkage-induced formation of microvillus-like protrusions. Hyperosmolarity-induced cell death was unaltered by ezrin knockdown or after phosphatidylinositol 3-kinase (PI3K) inhibition. In conclusion, ERM proteins are activated by osmotic shrinkage in a PtdIns(4,5)P(2)-dependent, NHE1-independent manner. This in turn mitigates the shrinkage-induced activation of NHE1, augments Rho activity, and may also contribute to F-actin rearrangement. In contrast, no evidence was found for the involvement of an NHE1-ezrin-PI3K-PKB pathway in counteracting shrinkage-induced cell death.
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PMID:Osmotic cell shrinkage activates ezrin/radixin/moesin (ERM) proteins: activation mechanisms and physiological implications. 1797 45


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