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)

Bombesin-like peptides, including the mammalian homologue gastrin-releasing peptides, are highly expressed and secreted by neuroendocrine cells in prostate carcinoma (PCa) tissues and are likely to be related to the progression of this disease. In the present study, we show that bombesin enhances the migration of androgen-independent PCa cells (PC-3) in vitro, while not affecting their adhesion to extracellular matrix proteins. The bombesin-increased motility of PC-3 cells occurs through its receptor, and, as shown with inhibitors, it likely requires activation of both protein tyrosine kinases (PTKs) and protein kinases C (PKCs). Because the focal adhesion kinase pp125FAK plays a key role in adhesion/motility and is highly expressed in advanced PCa, we examined whether in PC-3 cells bombesin signal transduction triggers the tyrosine phosphorylation of this PTK and of associated integrins and signaling proteins likely to be present in focal adhesion plaques. pp125FAK tyrosine phosphorylation was stimulated by bombesin and mimicked by PKC activation with the tumor-promotor phorbol 12-myristate-13-acetate (PMA). Moreover, this effect of bombesin on pp125FAK tyrosine phosphorylation requires the presence of both active PKC and cytoskeleton integrity since this signal was abolished by down-regulating PKCs induced by prolonged PMA treatment or by PKC inhibition with GF 109203X, as well as by disruption of the cytoskeleton with cytochalasin D. We also show that bombesin increases the tyrosine phosphorylation of a 95-kDa protein (pp95) which was co-immunoprecipitated with the alpha v and beta (3 and 5) subunits, forming integrin receptors with alpha v in PC-3 cells. The protein pp95 is distinct from the endogenously tyrosine-phosphorylated beta3 subunit. In addition, upon bombesin treatment, the beta1, beta3 and beta5 integrin subunits co-immunoprecipitated with pp125FAK and major phosphotyrosine (pY)-containing proteins of 125 and 68-70 kDa, likely corresponding to pp125FAK and paxillin. Together our data suggest that, in addition to PKC activation, tyrosine phosphorylation of pp125FAK and integrin-associated proteins may play an important role in bombesin signaling, triggering the processes of PCa cell motility and invasion.
 ...
PMID:Bombesin stimulates the motility of human prostate-carcinoma cells through tyrosine phosphorylation of focal adhesion kinase and of integrin-associated proteins. 924 95

The objective of this study is to establish normal ranges for the assessment of lung permeability, using 99mTc DTPA (diethylene triamine penta acetate) aerosol by measuring the half-time of transfer from the lung in asymptomatic HIV-positive patients. Also to audit the use of the test in the clinical management of outpatients with symptoms suggestive of Pneumocystis carinii pneumonia (PCP). A retrospective analysis of data from outpatients' notes for the audit of symptomatic patients, and prospective acquisition of 'normal' data for HIV-positive asymptomatic patients who were non-smokers and smokers was performed. Over a period of 8 years, DTPA scans were performed on 400 asymptomatic HIV-positive patients (121 non-smokers and 279 smokers) and 188 symptomatic HIV-positive patients with symptoms suggestive of PCP. A biphasic curve of transfer of 99mTc DTPA with a half-time of less than 4 min, was considered diagnostic of PCP. The mean half-times (+/-SEM) for asymptomatic non-smokers was 61.4 +/- 3 min and for smokers was 21.9 +/- 0.8 min. In the symptomatic patients, 106 were treated for PCP and in 97 (91.5%) of these, the transfer was biphasic. Of the remaining 82 patients with respiratory pathology other than PCP, 71 (86.6%) had normal scans. The results show that smokers may have abnormal baseline scans 16/ 279 (5.7%) and therefore a baseline scan before symptoms should be recorded or a higher false positive rate can be expected. The test is however highly sensitive for the detection of PCP and allows the attending physician to initiate PCP treatment without delay.
Int J STD AIDS 1997 Aug
PMID:Radioactively labelled diethylene triamine penta acetate lung scan in Pneumocystis carinii pneumonia and asymptomatic HIV-positive patients. 925 95

A panel of antibodies to the alphaIIbbeta3 integrin was used to promote adhesion of Chinese hamster ovary cells transfected with the alphaIIbbeta3 fibrinogen receptor. While some alphaIIbbeta3 antibodies were not able to induce p125 focal adhesion kinase (p125FAK) tyrosine phosphorylation, all the antibodies equally support cell adhesion but not spreading and assembly of actin stress fibers. Absence of stress fibers was also obtained by plating on antibodies directed to the hamster beta1 integrin. In contrast, cells plated on matrix proteins spread organizing actin stress fibers. Treatment with phorbol esters phorbol 12-myristate 13-acetate (PMA) induced cells to spread on antibodies-coated dishes but not to organize actin in stress fibers. The combination of PMA and cytotoxic necrotizing factor 1 (CNF1), a specific Rho activator, induced cell spreading and organization of stress fibers. PMA or the combination of PMA and CNF1 also increases tyrosine phosphorylation of p125FAK in response to antibodies that were otherwise unable to trigger this response. These data show that: 1) matrix proteins and antibodies differ in their ability to induce integrin-dependent actin cytoskeleton organization (while matrix induced stress fibers formation, antibodies did not); 2) p125FAK tyrosine phosphorylation is insufficient per se to trigger actin stress fibers formation since antibodies that activate p125FAK tyrosine phosphorylation did not lead to actin stress fibers assembly; and 3) the inability of anti-integrin antibodies to trigger stress fibers organization is overcome by concomitant activation of the protein kinase C (PKC) and Rho pathways; PKC activation leads to cell spreading and Rho activation is required to organize actin stress fibers.
 ...
PMID:Dissection of pathways implicated in integrin-mediated actin cytoskeleton assembly. Involvement of protein kinase C, Rho GTPase, and tyrosine phosphorylation. 926 1

Mechanical perturbation has been shown to modulate a wide variety of changes in second message signals and patterns of gene expression in osteoblasts. Embryonic chick osteoblasts were subjected to a dynamic spatially uniform biaxial strain (1.3% applied strain) at 0.25 Hz for a single 2-h period, and osteopontin (OPN), an Arg-Gly-Asp (RGD)-containing protein, was shown to be a mechanoresponsive gene. Expression of opn mRNA reached a maximal 4-fold increase 9 h after the end of the mechanical perturbation that was not inhibited by cycloheximide, thus demonstrating that mechanoinduction of opn expression is a primary response through the activation of pre-existing transcriptional factors. The signal transduction pathways, which mediated the increased expression of opn in response to mechanical stimuli, were shown to be dependent on the activation of a tyrosine kinase(s) and protein kinase A (PKA) or a PKA-like kinase. Selective inhibition of protein kinase C (PKC) had no effect on the mechanoinduction of osteopontin even though opn has been demonstrated to be an early response gene to phorbol 12-myristate 13-acetate (PMA) stimulation. Mechanotransduction was dependent on microfilament integrity since cytochalasin-D blocked the up-regulation of the opn expression; however, microfilament disruption had no effect on the PMA induction of the gene. The microtubule component of the cytoskeleton was not related to the mechanism of signal transduction involved in controlling opn expression in response to mechanical stimulation since colchicine did not block opn expression. Mechanical stimulus was shown to activate focal adhesion kinase (FAK), which specifically became associated with the cytoskeleton after mechanical perturbation, and its association with the cytoskeleton was dependent on tyrosine kinase activity. In conclusion, these results demonstrate that the signal transduction pathway for mechanical activation of opn is uniquely dependent on the structural integrity of the microfilament component of the cytoskeleton. In contrast, the PKC pathway, which also activates this gene in osteoblasts, acts independently of the cytoskeleton in the transduction of its activity.
 ...
PMID:Signal transduction of mechanical stimuli is dependent on microfilament integrity: identification of osteopontin as a mechanically induced gene in osteoblasts. 933 23

The tumor-promoting phorbol ester, phorbol 12-myristate 13-acetate (PMA), acutely stimulates the tyrosine phosphorylation of proteins of approximately 190, 120, and 70 kDa in the well differentiated Fao rat hepatoma cell line. This phosphorylation is dependent on protein kinase C (PKC) and is abolished by down-regulation of PKC or pretreatment with a PKC inhibitor. Purification of the 190-kDa tyrosine-phosphorylated protein revealed that it consists of both ErbB2 and ErbB3. Following PMA-induced tyrosine phosphorylation, ErbB2 and ErbB3 were able to associate with the SH2 domains of several signaling proteins including the p85alpha subunit of phosphatidylinositol 3-kinase, Syp, and Grb2. The 120-kDa protein phosphorylated in response to PMA consists of at least two proteins: focal adhesion kinase that exhibits a minor increase in tyrosine phosphorylation following treatment with PMA, and a major 120-kDa tyrosine-phosphorylated species in PMA-stimulated Fao cells which as yet is unidentified. Similarly, the 70-kDa tyrosine-phosphorylated protein also appears to represent more than one protein, including paxillin and a second protein of similar mobility which appears to be the major tyrosine phosphorylation in response to PMA. Both ErbB2 and paxillin also exhibit reduced migration on SDS-polyacrylamide gel electrophoresis following PMA treatment, suggesting that they are also phosphorylated on serine/threonine residues. The mobility shift of both of these proteins is abolished by treatment with inhibitors of PKC or mitogen-activated protein kinase/extracellular signal-related kinase kinase. These results suggest a novel mechanism of cross-talk between the serine/threonine kinase PKC and tyrosine phosphorylation pathways. The activation of ErbB2 and ErbB3 that is initiated by PMA may contribute to the tumor promoting activity of these compounds.
 ...
PMID:Cross-talk between phorbol ester-mediated signaling and tyrosine kinase proto-oncogenes. I. Activation of protein kinase C stimulates tyrosine phosphorylation and activation of ErbB2 and ErbB3. 938 71

The synthesis of water-soluble, unsymmetrical, trisulfonated zinc phthalocyanines (ZnPcS3) as single products of the ring expansion of boron tri(4-sulfo)subphthalocyanine (SubPc) is reported. The novel, water-soluble trisulfo-SubPcB(OH) was prepared via hydrolysis of the tris(4-chlorosulfonyl)SubPcB(Br) which in turn was obtained from the condensation of 4-(chlorosulfonyl)phthalonitrile with BBr3 in 1-chlorobenzene. A number of ZnPcS3 analogues were prepared via the reaction of S3SubPcB (OH) with different diiminoisoindoline derivatives of increasing hydrophobicity. The reaction proceeds at relative low temperature with acceptable yields. Metalation of free base Pc's with zinc acetate dihydrate afforded the corresponding zinc complexes. Photodynamic activities were measured against the EMT-6 mouse mammary tumor cell line and compared to those of the known ZnPcS3 and ZnPcS4. Added (t-Bu)benzo and (t-Bu)naphtho groups increased the in vitro cell photoinactivation efficacy of the ZnPcS3, whereas addition of a fourth sulfobenzo or bulky diphenylpyrazino group decreased the activity of the parent molecule. The (t-Bu)naphthotrisulfobenzoporphyrazine induced the best in vivo photodynamic tumor control which, combined with its good solubility and broad absorption spectrum, renders this compound an interesting dye for photodynamic applications in medicine.
 ...
PMID:Syntheses and photodynamic activities of novel trisulfonated zinc phthalocyanine derivatives. 939 70

Aggregation of the FcepsilonRI, a member of the immune receptor family, induces the activation of proteintyrosine kinases and results in tyrosine phosphorylation of proteins that are involved in downstream signaling pathways. Here we report that Pyk2, another member of the focal adhesion kinase family, was present in the RBL-2H3 mast cell line and was rapidly tyrosine-phosphorylated and activated after FcepsilonRI aggregation. Tyrosine phosphorylation of Pyk2 was also induced by the calcium ionophore A23187, by phorbol myristate acetate, or by stimulation of G-protein-coupled receptors. Adherence of cells to fibronectin dramatically enhanced the induced tyrosine phosphorylation of Pyk2. Although Src family kinases are activated by FcepsilonRI stimulation and tyrosine-phosphorylate the receptor subunits, the activation and tyrosine phosphorylation of Pyk2 were downstream of Syk. In contrast, tyrosine phosphorylation of Pyk2 by stimulation of G-protein-coupled receptors was independent of Syk. Therefore, the FcepsilonRI-induced tyrosine phosphorylation of Pyk2 is downstream of Syk and may play a role in cell secretion.
 ...
PMID:Activation of protein-tyrosine kinase Pyk2 is downstream of Syk in FcepsilonRI signaling. 940 54

We examined downstream signaling events that followed the exposure of PC12 cells to extracellular ATP and UTP, and we compared the effects of these P2 receptor agonists with those of growth factors and other stimuli. Based on early findings, we focused particular attention on the mitogen-activated protein (MAP) kinase pathway. ATP and/or UTP produced increases in tyrosine phosphorylation of multiple proteins, including p42 MAP (ERK2) kinase, related adhesion focal tyrosine kinase (RAFTK) (PYK2, CAKbeta), focal adhesion kinase (FAK), Shc, and protein kinase Cdelta (PKCdelta). MAP (ERK2) kinase activity (quantified by substrate phosphorylation) was increased by UTP, ATP, phorbol 12-myristate 13-acetate, ionomycin, and growth factors. UTP and ATP were equipotent (EC50 approximately 25 microM) in stimulating MAP kinase activity, suggesting that these effects were mediated via the Gi-linked P2Y2 (P2U) receptor. Consistent with this, the UTP- and ATP-promoted activation of MAP kinase was diminished in pertussis toxin-treated cells. Treatment of cells with pertussis toxin also reduced both the UTP-dependent increases in intracellular calcium ion concentration ([Ca2+]i) and the tyrosine phosphorylation of RAFTK. Similarly, when [Ca2+]i elevation was prevented using BAPTA and EGTA, the activation of MAP kinase by UTP and ionomycin was blocked, and the tyrosine phosphorylation of RAFTK was reduced. The UTP-promoted increase in MAP kinase activity was partially reduced in cells in which PKC was down-regulated, suggesting that both PKC-dependent and PKC-independent pathways were involved. PKCdelta, which increases MAP kinase activity in some systems, became tyrosine-phosphorylated within 15 s of exposure of cells to ATP or UTP; but epidermal growth factor, nerve growth factor, and insulin had little effect. UTP also promoted the association of Shc with Grb2. These results suggest that the P2Y2 receptor-initiated activation of MAP kinase was dependent on the elevation of [Ca2+]i, involved the recruitment of Shc and Grb2, and was mediated by RAFTK and PKC.
 ...
PMID:Activation of P2Y2 receptors by UTP and ATP stimulates mitogen-activated kinase activity through a pathway that involves related adhesion focal tyrosine kinase and protein kinase C. 944 69

The GH receptor is a member of the cytokine receptor superfamily. Studies in the 3T3-F442A mouse preadipocyte have shown that GH activates the Janus kinase (JAK2), the signal transducers and activators of transcription (STAT1, -3, and -5), and mitogen-activated protein (MAP) kinase. Our previous studies in the human IM-9 lymphocyte have shown that GH activates JAK2 and only STAT5 (not STAT1 or -3). In the studies presented here, we have investigated activation of the MAP kinase (MAPK) pathway in the IM-9 lymphocyte. Western blotting with antiphosphotyrosine-, anti-MAPK-, and anti-phospho-MAPK-specific antibodies as well in vitro kinase assays using a synthetic peptide substrate demonstrate that although GH (200 ng/ml) activates MAPK in 3T3-F442A cells (at 5 and 10 min of treatment), it does not activate MAPK in IM-9 lymphocytes at time points ranging from 5-60 min. Nevertheless, the phorbol ester phorbol 12-myristate 13-acetate (50 ng/ml) does activate MAPK in the IM-9 cell, and immunoprecipitation with specific antibodies indicates that this activation occurs through c-Raf-1. Although the 52- and 66-kDa forms of the adapter protein Shc are tyrosine phosphorylated in response to GH treatment in 3T3-F442A cells, we demonstrate that the predominant forms in IM-9 cells are the 52- and 46-kDa forms, and neither is tyrosine phosphorylated in response to GH. These studies further elucidate the differential signaling by GH in two cell types.
 ...
PMID:Growth hormone stimulation of the mitogen-activated protein kinase pathway is cell type specific. 952 83

Freshly isolated human monocytes do not express p125(FAK) but upon adherence to substrata activate the highly related calcium-dependent tyrosine kinase (CADTK), also known as Pyk2, CAKbeta, RAFTK, and FAK2. The monocyte CADTK was 5 kDa smaller than protein from epithelial cells; isolation and sequencing of the monocyte CADTK cDNA revealed a predicted 42-amino acid deletion between the two proline-rich domains of the enzyme. The nucleic acid sequence suggests that the deletion is caused by alternative RNA splicing. This species was also found in T and B lymphocytes and appears to be the predominant form of cytoskeletal associated tyrosine kinase in non-neoplastic, circulating, hematopoietic cells. CADTK was not activated when monocytes maintained in suspension were treated with agents that produce an intracellular calcium (thapsigargin) or protein kinase C (phorbol 12-myristate 13-acetate) signal including a chemokine, RANTES, that binds to the HIV co-receptor, CCK5. In contrast, monocyte adherence to tissue culture plastic-stimulated CADTK tyrosine phosphorylation, a process that was enhanced by thapsigargin, phorbol 12-myristate 13-acetate, and RANTES but that was completely blocked by preincubation with cytochalasin D. When compared with plastic, adherence to fibronectin- or collagen-coated surfaces produced only minimal CADTK activation but permitted significant stimulation by added thapsigargin. These data suggest that in a cell type that lacks p125(FAK), CADTK plays an early role in post-adherence signaling. Its activation involves two stages, cytoskeletal engagement, which is permissive, and co-stimulatory signals (calcium or protein kinase C) generated by extensive cell surface engagement, agonists, or inflammatory chemokines.
 ...
PMID:A calcium-dependent tyrosine kinase splice variant in human monocytes. Activation by a two-stage process involving adherence and a subsequent intracellular signal. 954 57


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>