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)

Intestinal cell growth and differentiation are tightly regulated by growth factors and extracellular matrix components along the crypt-villus axis. We previously described enterophilin-1 (Ent-1) as a new intestinal protein associated with growth arrest and enterocyte differentiation. Ent-1 interacted with sorting nexin 1 and decreased cell surface epidermal growth factor receptor. Because beta(1) integrins are mostly found in vivo in the proliferative crypt cells, we investigated the role of Ent-1 in the fate of beta(1) integrin subunits. In undifferentiated intestinal Caco-2 cells, overexpression of Ent-1 induces a marked decrease of alpha(5)beta(1) integrin pools, whereas alpha(2)beta(1) integrin is weakly affected. Conversely, overexpression of sorting nexin 1 has no effect on integrin levels despite its ability to interact with Ent-1. Interestingly, we identified focal adhesion kinase as a new Ent-1 partner using yeast two-hybrid screening and co-precipitation experiments. Furthermore by confocal microscopy, we observed that Ent-1 and beta(1) integrins partly co-localize on vesicular structures, suggesting a role for Ent-1 in integrin trafficking. Because focal adhesion kinase is able to bind both Ent-1 and beta(1) integrins, the kinase might act as a molecular bridge between the two proteins. Altogether, these results support a role of Ent-1 in regulating beta(1) integrin expression that could favor intestinal differentiation.
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PMID:Enterophilin-1 interacts with focal adhesion kinase and decreases beta1 integrins in intestinal Caco-2 cells. 1463 Sep 35

Many proteins, including cell-surface receptors, extracellular matrix (ECM) proteins and intracellular signalling systems, are constructed from a relatively small number of domains or modules. Modularity provides biological systems with a convenient way of presenting binding sites on a stable protein scaffold, in the correct position for function; it also allows regulation by module rearrangement. Knowledge about modular proteins is increasing rapidly because of good databases and more systematic approaches to protein expression and structure determination. There have been a number of important recent structures of modular proteins at the cell surface, including the low-density-lipoprotein receptor, epidermal growth factor receptor and an integrin. These and other studies show how the main task of structural biology has moved from determination of module structures to the task of assessing how modular proteins are regulated and how they bind their various ligands. These aspects are illustrated here by recent studies of modular proteins carried out in our laboratory and elsewhere. Examples will include studies of ECM proteins, such as fibronectin, and proteins associated with focal adhesion complexes that involve fibronectin, integrins and various intracellular modular proteins, such as focal adhesion kinase, Src family kinases, talin and paxillin.
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PMID:Modular proteins at the cell surface. 1464 Oct 6

Cancer metastasis is a significant problem and a tremendous challenge to drug discovery relative to identifying key therapeutic targets as well as developing breakthrough medicines. Recent progress in unravelling the complex molecular circuitry of cancer metastasis, including receptors, intracellular proteins and genes, is highlighted. Furthermore, recent advances in drug discovery to provide novel proof-of-concept ligands, in vivo effective lead compounds and promising clinical candidates, are summarised. Such drug discovery efforts illustrate the integration of functional genomics, cell biology, structural biology, drug design, molecular/cellular screening and chemical diversity (e.g., small molecules, peptides/peptidomimetics, natural products, antisense, vaccines and antibodies). Promising therapeutic targets for cancer metastasis have been identified, including Src, focal adhesion kinase, the integrin receptor, the vascular endothelial growth factor receptor, the epidermal growth factor receptor, Her-2/neu, c-Met, Ras/Rac GTPases, Raf kinase, farnesyl diphosphate synthase (i.e., amino-bisphosphonate therapeutic target) and matrix metalloproteases within the context of their implicated functional roles in cancer growth, invasion, angiogenesis and survival at secondary sites. Clinical and preclinical drug discovery is described and emerging small-molecule inhibitors of protein kinases are highlighted.
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PMID:Cancer metastasis therapeutic targets and drug discovery: emerging small-molecule protein kinase inhibitors. 1468 Apr 49

EGFR (epidermal growth factor receptor) is a transmembrane glycoprotein highly expressed in head and neck squamous cell carcinoma (HNSCC). Once triggered by ligands, tyrosine kinase located at their inner part is phosphorylated, initiating signal transduction pathways towards the nucleus. Two categories of EGFR inhibitors are affordable: the former group includes monoclonal antibodies whereas the latter regards tyrosine kinase inhibitors (ITK). Acting more as cytostatic than cytotoxic agents, they may potentiate both chemotherapy (CT) and radiation therapy (RT). Characterized by a spectrum of toxicity that does not overlap that of CT or RT, they may be associated with these treatments. First clinical trials have demonstrated the feasibility of their administration. Side-effects merely consist of skin reactions and digestive symptoms; their intensity is generally mild and they resolve at the completion of treatment. As of yet, response rates are sometimes astounding but are still disparate. Randomized studies are ongoing. A better definition of EGFR status is warranted. Other data regarding interactions between her-family members, ligands parameters and the cascade regulation of signal transduction would certainly enable to better define the clinical applications of this new therapeutical approach.
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PMID:[Targeting of epidermal growth factor receptor and applications in ORL cancer]. 1476 43

Signal transducers and activators of transcription factors (STATs) mediate many of the cellular responses that occur following cytokine, growth factor, and hormone signaling. STATs are activated by tyrosine and serine phosphorylation, which normally occurs as a tightly regulated process. Dysregulated STAT activity may facilitate oncogenesis, as constitutively activated STATs have been found in many human tumors as well as in v-abl- and v-src-transformed cell lines. Pyk2 is a member of the focal adhesion kinase family and can be activated by c-Src, epidermal growth factor receptor (EGFR), Janus kinase 1, tyrosine kinases, and G-protein-coupled receptor signaling. Although Pyk2 has been implicated in Janus kinase-dependent activation of MAPK and Stat1, no role for Pyk2 in the activation of other STAT proteins has been ascribed. Here, we provide evidence that Pyk2, along with c-Src, facilitates EGFR-mediated Stat3 activation. Pyk2 expression in HeLa cells induces Stat3 reporter gene activation and Stat3 phosphorylation on amino acid residues Tyr-705 and Ser-727. Together Pyk2 and c-Src potently activate Stat3, and Pyk2 enhances Stat3-induced cell proliferation. Moreover, the expression of a dominant negative version of Pyk2 impairs c-Src-induced Stat3 activation and cell proliferation. The treatment of A431 cells with EGF results in the recruitment of c-Src, Pyk2, and Stat3 to the EGFR and the phosphorylation of c-Src, Pyk2, and Stat3. Expression of constructs for dominant negative forms of either Pyk2 or c-Src impair EGF-induced Stat3 phosphorylation. These results indicate that Pyk2 facilitates EGFR- and c-Src-mediated Stat3 activation, thereby implicating Pyk2 activation as a potential co-mediator in triggering Stat3-induced oncogenesis.
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PMID:Pyk2 amplifies epidermal growth factor and c-Src-induced Stat3 activation. 1496 38

Opioid peptides exert diverse physiological functions through their cognate receptors. One subtype of the opioid receptors, kappa-opioid receptor, is endogenously expressed in human monocytic THP-1 cells. Stimulation of the THP-1 cells with a kappa-opioid receptor-selective agonist exerted a Gi-dependent activation of c-Jun N-terminal kinase (JNK). To further investigate the signaling mechanism by which the kappa-opioid receptor regulates JNK activity, heterologous expression assays in COS-7 cells were utilized. Overexpression of Galphat in COS-7 cells clearly suppressed kappa-opioid receptor-stimulated JNK activity, indicating that the pathway is primarily regulated by Gbetagamma. In both THP-1 and transfected COS-7 cells, pretreatment of the selective Src family kinase inhibitor pyrazolopyrimidine PP1 abolished the JNK activation, whereas the epidermal growth factor receptor inhibitor AG1478 [N-(3-chlorophenyl)-6,7-dimethoxy-4-quinazolinanine] failed to do that. Furthermore, the JNK activation in response to kappa-opioid receptor was suppressed by an autophosphorylation-resistant mutant of focal adhesion kinase (FAK). Consistently, activated kappa-opioid receptor induced Src stimulation and FAK autophosphorylation and promoted the formation of Src-FAK complex. The participation of small GTPases as well as a guanine nucleotide exchange factor was also implicated because dominant-negative mutants of Rac, Cdc42, and Son-of-sevenless (Sos) attenuated the agonist-induced activation of JNK. These studies demonstrate that the activation of JNK by kappa-opioid receptors is routed via Gbetagamma, Src, FAK, Sos, Rac, and Cdc42.
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PMID:Kappa-opioid receptor signals through Src and focal adhesion kinase to stimulate c-Jun N-terminal kinases in transfected COS-7 cells and human monocytic THP-1 cells. 1499 48

Cannabinoids, the active components of marijuana and their endogenous counterparts were reported as useful analgetic agents to accompany primary cancer treatment by preventing nausea, vomiting, and pain and by stimulating appetite. Moreover, they have been shown to inhibit cell growth and to induce apoptosis in tumor cells. Here, we demonstrate that anandamide, Delta(9)-tetrahydrocannabinol (THC), HU-210, and Win55,212-2 promote mitogenic kinase signaling in cancer cells. Treatment of the glioblastoma cell line U373-MG and the lung carcinoma cell line NCI-H292 with nanomolar concentrations of THC led to accelerated cell proliferation that was completely dependent on metalloprotease and epidermal growth factor receptor (EGFR) activity. EGFR signal transactivation was identified as the mechanistic link between cannabinoid receptors and the activation of the mitogen-activated protein kinases extracellular signal-regulated kinase 1/2 as well as prosurvival protein kinase B (Akt/PKB) signaling. Depending on the cellular context, signal cross-communication was mediated by shedding of proAmphiregulin (proAR) and/or proHeparin-binding epidermal growth factor-like growth factor (proHB-EGF) by tumor necrosis factor alpha converting enzyme (TACE/ADAM17). Taken together, our data show that concentrations of THC comparable with those detected in the serum of patients after THC administration accelerate proliferation of cancer cells instead of apoptosis and thereby contribute to cancer progression in patients.
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PMID:Cannabinoids induce cancer cell proliferation via tumor necrosis factor alpha-converting enzyme (TACE/ADAM17)-mediated transactivation of the epidermal growth factor receptor. 1502 28

We have demonstrated previously that the EGFR (epidermal growth factor receptor) is a calmodulin (CaM)-binding protein. To establish whether or not the related receptor ErbB2/Neu/HER2 also binds CaM, we used human breast adenocarcinoma SK-BR-3 cells, because these cells overexpress this receptor thus facilitating the detection of this interaction. In the present paper, we show that ErbB2 could be pulled-down using CaM-agarose beads in a Ca2+-dependent manner, as detected by Western blot analysis using an anti-ErbB2 antibody. ErbB2 was also isolated by Ca2+-dependent CaM-affinity chromatography. We also demonstrate using an overlay technique with biotinylated CaM that CaM binds directly to the immunoprecipitated ErbB2. The binding of biotinylated CaM to ErbB2 depends strictly on the presence of Ca2+, since it was prevented by the presence of EGTA. Moreover, the addition of an excess of free CaM prevents the binding of its biotinylated form, demonstrating that this was a specific process. We excluded any interference with the EGFR, as SK-BR-3 cells express considerably lower levels of this receptor, and no detectable EGFR signal was observed by Western blot analysis in the immunoprecipitated ErbB2 preparations used to perform the overlay assays with biotinylated CaM. We also demonstrate that treating living cells with W7 [N-(6-aminohexyl)-5-chloro-1-naphthalenesulphonamide], a cell-permeant CaM antagonist, down-regulates ErbB2 phosphorylation, and show that W7 does not interfere non-specifically with the activity of ErbB tyrosine kinases. We also show that W7 inhibits the phosphorylation (activation) of both ERK1/2 (extracellular-signal-regulated kinases 1 and 2) and Akt/PKB (protein kinase B), in accordance with the inhibition observed in ErbB2 phosphorylation. In contrast, W7 treatment increased the phosphorylation (activation) of CREB (cAMP-response-element-binding protein) and ATF1 (activating transcription factor-1), two Ca2+-sensitive transcription factors that operate downstream of these ErbB2 signalling pathways, most likely because of the absence of calcineurin activity. We conclude that ErbB2 is a new CaM-binding protein, and that CaM plays a role in the regulation of this receptor and its downstream signalling pathways in vivo.
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PMID:The ErbB2/Neu/HER2 receptor is a new calmodulin-binding protein. 1508 Jul 92

Positive and negative regulation of cytokines such as IFN-gamma are key to normal homeostatic function. Negative regulation of IFN-gamma in cells occurs via proteins called suppressors of cytokine signaling (SOCS)1 and -3. SOCS-1 inhibits IFN-gamma function by binding to the autophosphorylation site of the tyrosine kinase Janus kinase (JAK)2. We have developed a short 12-mer peptide, WLVFFVIFYFFR, that binds to the autophosphorylation site of JAK2, resulting in inhibition of its autophosphorylation as well as its phosphorylation of IFN-gamma receptor subunit IFNGR-1. The JAK2 tyrosine kinase inhibitor peptide (Tkip) did not bind to or inhibit tyrosine autophosphorylation of vascular endothelial growth factor receptor or phosphorylation of a substrate peptide by the protooncogene tyrosine kinase c-src. Tkip also inhibited epidermal growth factor receptor autophosphorylation, consistent with the fact that epidermal growth factor receptor is regulated by SOCS-1 and SOCS-3, similar to JAK2. Although Tkip binds to unphosphorylated JAK2 autophosphorylation site peptide, it binds significantly better to tyrosine-1007 phosphorylated JAK2 autophosphorylation site peptide. SOCS-1 only recognizes the JAK2 site in its phosphorylated state. Thus, Tkip recognizes the JAK2 autophosphorylation site similar to SOCS-1, but not precisely the same way. Consistent with inhibition of JAK2, Tkip inhibited the ability of IFN-gamma to induce an antiviral state as well as up-regulate MHC class I molecules on cells at a concentration of approximately 10 microM. This is similar to the K(d) of SOCS-3 for the erythropoietin receptor. These data represent a proof-of-concept demonstration of a peptide mimetic of SOCS-1 that regulates JAK2 tyrosine kinase function.
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PMID:Characterization of a peptide inhibitor of Janus kinase 2 that mimics suppressor of cytokine signaling 1 function. 1518 30

Expression of nNOS mRNA was found in normal human and mouse skin tissue. Upon wounding, we observed a rapid downregulation of nNOS mRNA and protein in wounds of mice; however, when repair continued, nNOS mRNA was strongly upregulated and nNOS protein expression peaked at late stages of healing. Immunohistochemistry revealed wound keratinocytes as the cellular source of nNOS. In line with the in vivo situation, we found a basal expression of nNOS in the human keratinocyte cell line HaCaT. A marked stimulation of nNOS expression in the cells was achieved with epidermal growth factor receptor (EGFR) ligands such as epidermal growth factor (EGF), heparin-binding EGF, transforming growth factor-alpha and two alternate splicing forms of the neuregulin gene. EGF-induced induction of nNOS was completely inhibited by the specific EGFR antagonist PD153035 and by the EGFR and Janus kinase 2/3 inhibitor AG490. Activation of EGFR might contribute to the observed upregulation of nNOS also in skin repair, as we found a spatial and temporal correlation of phosphorylated EGFR (Y1173) with nNOS expression at the wound site. Thus, in addition to the inducible- and endothelial-type NOS isoforms, also nNOS expression is regulated in the process of cutaneous wound repair.
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PMID:The neuronal nitric oxide synthase is upregulated in mouse skin repair and in response to epidermal growth factor in human HaCaT keratinocytes. 1519 53


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