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: UMLS:C0001511 (Adhesion)
5,955 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CRKL, an SH2-SH3-SH3 adapter protein, is one of the major tyrosine phosphoproteins detected in primary leukemic neutrophils from patients with CML. CRKL binds directly to BCR/ABL through its N-terminal SH3 domain, suggesting it may be involved in BCR/ABL signal transduction. However, the biological function of CRKL in either normal or leukemic cells is still largely unknown. In this study, we have examined the effects of overexpressing full length or deletion mutants of CRKL in hematopoietic cell lines. Full length, SH2- and SH3(N)-domain deletion mutants of CRKL were transfected into an interleukin-3-dependent hematopoietic cell line, Ba/F3, and 3-5 individual sublines which stably overexpressed each transgene were obtained [Ba/F-CRKL, Ba/F-CRKL deltaSH2, and Ba/F-CRKL deltaSH3(N)]. The growth properties of these transfected cells in the presence or absence of IL-3 were not different from mock transfected or untransfected Ba/F3 cells. However, Ba/F3 cells overexpressing full length CRKL, but not deletion mutants of CRKL, were found to have an increase in their ability to bind to fibronectin-coated surfaces. Further, expression of full length, but not deltaSH2- or deltaSH3-CRKL deletion mutants, was found to alter cell morphology on fibronectin-coated plates, an effect which was further enhanced by certain kinds of stress stimuli, such as ionizing radiation. Similar results were obtained when CRKL was transiently overexpressed in Ba/F3 cells, and were also obtained in a second IL-3 dependent hematopoietic cell line, 32Dcl3. Adhesion to fibronectin was blocked by anti-beta1 integrin monoclonal antibody, but overexpression of CRKL did not affect surface expression of beta1 integrins, nor did it spontaneously induce expression of the beta1 integrin 'activation' epitope recognized by the 9EG7 monoclonal antibody. These data suggest a role for CRKL in signaling pathways which regulate adhesion to fibronectin.
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PMID:Involvement of the adapter protein CRKL in integrin-mediated adhesion. 1036 55

Focal adhesion kinase (FAK or pp125FAK) is a cytosolic protein tyrosine kinase which plays an important role in integrin-mediated signal transduction. Adhesion of cells to the substratum correlates with an increase in tyrosine phosphorylation of FAK as well as an associated protein, paxillin. In this report we show that the tyrosine phosphorylation of FAK and paxillin are decreased during dibutyryl cyclic AMP-induced (dB-cAMP) process formation in astrocytes. When astrocytes in suspension are treated with dB-cAMP, no alteration in morphology or tyrosine phosphorylation is observed, suggesting that both phenomena are linked and adhesion dependent. Furthermore, genistein, a tyrosine kinase inhibitor, can induce process formation in such cells, underscoring the significance of protein tyrosine kinases in maintaining the morphology of adherent cells. Finally, endothelin-1, a vasopeptide which is known to inhibit process formation in astrocytes, inhibited the tyrosine dephosphorylation of proteins associated with dB-cAMP treatment. These results suggest that the formation of asymmetric processes in astrocytes results from a coordinated set of alterations in the actin cytoskeleton as well as the adhesion of the cell to the substratum. Modification of the properties of such molecules is required for process formation and the dynamic modulation of astrocytic morphology in vitro and in vivo.
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PMID:Dibutyryl cyclic AMP-induced process formation in astrocytes is associated with a decrease in tyrosine phosphorylation of focal adhesion kinase and paxillin. 1036 13

Adhesion is associated with tyrosine phosphorylation in many types of cells. Although macrophages are known to adhere and phagocytose foreign particles, the signal transduction pathway of macrophages in response to adhesion to the foreign substrate has not been fully investigated. In the present study we investigated tyrosine-phosphorylated proteins and phosphorylation of paxillin in alveolar macrophages (AMs) following adhesion to a plastic substrate. Adhesion to a plastic dish resulted in tyrosine phosphorylation of a 68 000 MW protein, which was shown, by immunoprecipitation and immunoblotting in the present study, to be a rat Syk kinase. Treatment with erbstatin reduced both tyrosine phosphorylation of Syk and adherence of AMs, while treatment with cytochalasin B inhibited spreading of AMs but did not inhibit tyrosine phosphorylation of Syk. These results suggest that tyrosine phosphorylation of Syk plays an important role in adhesion of AMs to the plastic substrate, but not in AM spreading. Paxillin is known to be tyrosine phosphorylated following adhesion to the extracellular matrix in many types of cells. However, paxillin appeared to be serine/threonine phosphorylated rather than tyrosine phosphorylated following adhesion of AMs to the plastic substrate. Treatment with A23187 (a calcium ionophore), but not phorbol 12-myristate 13-acetate (PMA; a protein kinase C stimulator), induced tyrosine phosphorylation of Syk in non-adherent AMs. Treatment with either A23187 or PMA caused electromobility changes of paxillin that were mainly a result of serine/threonine phosphorylation. These results suggest that adhesion to the plastic substrate leads to two differently regulated events in AMs: tyrosine phosphorylation of Syk and serine/threonine phosphorylation of paxillin, both of which are probably mediated by an increase in intracellular calcium.
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PMID:Syk and paxillin are differentially phosphorylated following adhesion to the plastic substrate in rat alveolar macrophages. 1044 62

Adhesion of platelets to collagen in damaged blood vessels or ruptured atherosclerotic plaques is important in hemostasis and arterial thrombosis. Adhesion to collagen results in secretion of granule contents and formation of thromboxane A2; thromboxane A2 and released ADP synergistically promote aggregation around platelets adherent to collagen. Ethanol inhibits collagen-induced platelet aggregation, secretion, arachidonate mobilization, and thromboxane A2 formation but does not inhibit platelet adhesion to de-endothelialized rabbit aortae. We investigated whether ethanol affects the initial signalling events and responses of platelets adherent to collagen, independent of the actions of secondary agonists. Suspensions of washed human platelets, labelled by incorporation of [3H]oleate into phospholipids, were used to measure platelet adhesion to collagen by a filtration method; studies were done in the presence of an ADP-removing system and blockers of receptors for thromboxane A2, platelet-activating factor, serotonin, and fibrinogen. Ethanol (87 mM) did not affect the rate or extent of platelet adhesion to collagen or secretion of [14C]serotonin from prelabelled platelets adherent to collagen, but ethanol did inhibit thromboxane A2 formation. Previous studies showed that ethanol does not affect platelet stimulation by arachidonate, leading to the suggestion that reduced mobilization of arachidonate, rather than inhibition of its conversion to thromboxane A2, is responsible for inhibition by ethanol of thromboxane A2 formation. Here, we show by a gel mobility shift assay and immunoblotting, that ethanol delays the collagen-induced increase in the phosphorylation of cytosolic phospholipase A2, the enzyme responsible for arachidonate mobilization. However, ethanol has no effect on collagen-induced tyrosine phosphorylation of phospholipase Cgamma2, determined by immunoprecipitation and immunoblotting. Thus, ethanol's effect on signal transduction in collagen-adherent platelets occurs distal to phosphorylation of phospholipase Cgamma2 but proximal to phosphorylation of cytosolic phospholipase A2.
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PMID:Effects of ethanol on platelet responses associated with adhesion to collagen. 1052 8

Factor J (FJ) is a cationic glycoprotein with inhibitory activity in vitro against both classical and alternative pathways of complement activation. Recently FJ has been implicated in adhesion to several cell lines, through a membrane receptor identified as nucleolin. In the present work we study the events that follow the binding of FJ to cells. After incubation of K562 with FJ, this protein was internalized actively and localized in the cytoplasm and nucleus. Adhesion to immobilized FJ induced tyrosine phosphorylation of several intracellular proteins in Jurkat cell line with a similar pattern to that induced by fibronectin (FN), an extracellular matrix protein. This effect was maximal at 5 min and decreased after 10 min, and inhibited by anti-FJ monoclonal antibody (mAb). These results suggest that the binding of FJ to cells may play an important role in transduction of biochemical signals across the plasma membrane to the cell interior.
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PMID:Internalization of factor J and cellular signalization after factor J-cell interaction. 1058 Nov 63

The integrin alpha(9)beta(1) mediates cell adhesion to tenascin-C and VCAM-1 by binding to sequences distinct from the common integrin-recognition sequence, arginine-glycine-aspartic acid (RGD). A thrombin-cleaved NH(2)-terminal fragment of osteopontin containing the RGD sequence has recently been shown to also be a ligand for alpha(9)beta(1). In this report, we used site-directed mutagenesis and synthetic peptides to identify the alpha(9)beta(1) recognition sequence in osteopontin. alpha(9)-transfected SW480, Chinese hamster ovary, and L-cells adhered to a recombinant NH(2)-terminal osteopontin fragment in which the RGD site was mutated to RAA (nOPN-RAA). Adhesion was completely inhibited by anti-alpha(9) monoclonal antibody Y9A2, indicating the presence of a non-RGD alpha(9)beta(1) recognition sequence within this fragment. Alanine substitution mutagenesis of 13 additional conserved negatively charged amino acid residues in this fragment had no effect on alpha(9)beta(1)-mediated adhesion, but adhesion was dramatically inhibited by either alanine substitution or deletion of tyrosine 165. A synthetic peptide, SVVYGLR, corresponding to the sequence surrounding Tyr(165), blocked alpha(9)beta(1)-mediated adhesion to nOPN-RAA and exposed a ligand-binding-dependent epitope on the integrin beta(1) subunit on alpha(9)-transfected, but not on mock-transfected cells. These results demonstrate that the linear sequence SVVYGLR directly binds to alpha(9)beta(1) and is responsible for alpha(9)beta(1)-mediated cell adhesion to the NH(2)-terminal fragment of osteopontin.
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PMID:The integrin alpha(9)beta(1) binds to a novel recognition sequence (SVVYGLR) in the thrombin-cleaved amino-terminal fragment of osteopontin. 1059 24

Related Adhesion Focal Tyrosine Kinase (RAFTK; also known as Pyk2), is a member of the Focal Adhesion Kinase (FAK) subfamily and is activated by TNF alpha, UV light and increases in intracellular calcium levels. However, the function of RAFTK remains largely unknown. Our previous studies demonstrated that treatment with dexamethasone (Dex), ionizing radiation (IR), and anti-Fas mAb induces apoptosis in multiple myeloma (MM) cells. In the present study, we examined the potential role of RAFTK during induction of apoptosis in human MM cells triggered by these three stimuli. Dex-induced apoptosis, in contrast to apoptosis triggered by anti-Fas mAb or IR, is associated with activation of RAFTK. Transient overexpression of RAFTK wild type (RAFTK WT) induces apoptosis, whereas transient overexpression of Kinase inactive RAFTK (RAFTK K-M) blocks Dex-induced apoptosis. In contrast, transient overexpression of RAFTK K-M has no effect on apoptosis triggered by IR or Fas. In Dex-resistant cells, Dex does not trigger either RAFTK activation or apoptosis. Finally, interleukin-6 (IL-6), a known survival factor for MM cells, inhibits both activation of RAFTK and apoptosis of MM.1S cells triggered by Dex. Our studies therefore demonstrate Dex-induced RAFTK-dependent, and IR or Fas induced RAFTK-independent apoptotic signaling cascades in MM cells.
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PMID:RAFTK/PYK2-dependent and -independent apoptosis in multiple myeloma cells. 1059 81

The bacterial endotoxin LPS is a potent stimulator of monocyte and macrophage activation and induces adhesion of monocytes. Morphological changes in response to LPS have not been characterized in detail, however, nor have the signaling pathways mediating LPS-induced adhesion been elucidated. We have found that LPS rapidly induced adhesion and spreading of peripheral blood monocytes, and that this was inhibited by the Src family kinase inhibitor PP1 and the phosphatidylinositide 3-kinase inhibitor LY294002. LPS also stimulated actin reorganization, leading to the formation of filopodia, lamellipodia, and membrane ruffles in Bac1 mouse macrophages. Proline-rich tyrosine kinase 2 (Pyk2), a tyrosine kinase related to focal adhesion kinase, and paxillin, a cytoskeletal protein that interacts with Pyk2, were both tyrosine phosphorylated in response to LPS in monocytes and macrophages. Both tyrosine phosphorylation events were inhibited by PP1 and LY294002. Adhesion also stimulated tyrosine phosphorylation of Pyk2 and paxillin in monocytes, and this was further enhanced by LPS. Finally, Pyk2 and paxillin colocalized within membrane ruffles in LPS-stimulated cells. These results indicate that LPS stimulation of monocytes and macrophages results in rapid morphological changes and suggest that Pyk2 and/or paxillin play a role in this response.
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PMID:Lipopolysaccharide induces actin reorganization and tyrosine phosphorylation of Pyk2 and paxillin in monocytes and macrophages. 1065 55

Adhesion of human monocytes (MOs) results in the rapid transcriptional activation of cytokine genes that are dependent on nuclear factor (NF)-kappaB. Several pathways leading to activation of NF-kappaB have been described, including those involving reactive oxygen intermediates (ROIs) and members of the mitogen-activated protein (MAP) kinase superfamily. To investigate the involvement of tyrosine phosphorylation (TP) and oxidant generation in interleukin (IL)-8 and GRO messenger RNA induction, MOs and human alveolar macrophages (AMs) were adhered to plastic or exposed to a particulate pollutant, residual oil fly ash (ROFA). Both stimuli caused rapid TP and ROI production in MOs and AMs. However, neither NF-kappaB translocation nor IL-8 gene induction occurred in adhered or ROFA-exposed AMs. Analysis of MAP kinase activation found phosphorylation of Jun amino-terminal kinase (JNK) and p38 in the AMs, but not of extracellular regulated kinase/MAP kinase (ERK/MAPK). AMs stimulated with lipopolysaccharide activated ERK/MAPK, in addition to JNK and p38, and showed translocation of NF-kappaB. In contrast to AMs, MO adhesion or exposure to ROFA particles in suspension rapidly activated p38, JNK, and ERK/MAPK, and activated NF-kappaB binding as well as IL-8 mRNA expression. Pretreatment with the tyrosine kinase inhibitors genistein or herbimycin A before adherence had no effect on transcriptional activation in MOs, whereas adherence and ROFA-induced oxidant generation was inhibited in both MOs and AMs. Taken together, these data indicate that NF-kappaB activation or generalized transcriptional activation of cytokine genes are independent of changes in oxidant stress imposed on phagocytes by adhesion. Furthermore, the data suggest that certain environmental responses in AMs may be uncoupled from activation of NF-kappaB.
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PMID:Adhesion and pollution particle-induced oxidant generation is neither necessary nor sufficient for cytokine induction in human alveolar macrophages. 1065 41

CD9, a widely expressed membrane protein of the tetraspanin family, has been implicated in diverse functions, such as signal transduction, cell adhesion, and cell motility. We tested the effects of an anti-CD9 monoclonal antibody (ALMA.1) on the migration and proliferation of human vascular endothelial cells (ECs) during repair of an in vitro mechanical wound mimicking angiogenic processes. ALMA.1 induced dose-dependent inhibition of wound repair with a 35+/-1.5% decrease at 20 microg/mL. Only cell migration was affected, because the rate of proliferation of ECs at the lesion margin was not modified and because the inhibition of repair was also observed for nonproliferating irradiated ECs. Monoclonal antibodies against CD63 tetraspanin (H5C6) and control mouse IgG (MOPC-21) were inactive. CD9, one of the most abundant proteins at the surface of ECs, colocalized with beta(1) or beta(3) integrins on EC membranes in double-labeling immunofluorescence experiments with ALMA.1 and an anti-beta(1) (4B4) or anti-beta(3) (SDF.3) monoclonal antibody. Moreover, ALMA.1 and 4B4 had additive inhibitory effects on lesion repair, whereas 4B4 alone also inhibited EC proliferation. In transmembrane Boyden-type assays, ALMA.1 induced dose-dependent inhibition of EC migration toward fibronectin and vitronectin with 45+/-6% and 31+/-10% inhibition, respectively, at 100 microg/mL. 4B4 inhibited migration toward fibronectin at 10 microg/mL but had no effect in the case of vitronectin. Adhesion of ECs to immobilized anti-CD9 monoclonal antibodies induced tyrosine-phosphorylated protein levels similar to those observed during interactions with beta(1) or beta(3) integrins. These results point to the involvement of CD9 in EC adhesion and migration during lesion repair and angiogenesis, probably through cooperation with integrins. As such, CD9 is a potential target to inhibit angiogenesis in metastatic and atherosclerotic processes.
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PMID:CD9 participates in endothelial cell migration during in vitro wound repair. 1066 31


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