Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

RON (Receptuer d'Origine Nantaise) is a member of the MET receptor tyrosine kinase family. RON is expressed in various cell types including macrophages, epithelial and hematopoietic cells. Its ligand, macrophage stimulating protein (MSP, also known as hepatocyte growth factor-like protein), is a multifunctional factor regulating cell growth and survival, adhesion and motility, cytokine production and phagocytosis. Accumulated data indicate that in addition to the regulation of normal cell functions, RON can be involved in cancer development and progression: (i). RON is overexpressed and constitutively active in some primary tumors and tumor cell lines; (ii). experimental mutations of RON cause oncogenic cell transformation, and (iii). RON mediates susceptibility to Friend-virus-induced erythroleukemia in mice. Constitutive activation of intracellular signaling pathways such as the PI-3 kinase/AKT, beta-catenin, MAPK and JNK pathways may underlie the molecular mechanism of RON-mediated oncogenic cell transformation. The present review describes RON-activated signaling pathways, which may play an important role in tumor formation and metastasis.
 ...
PMID:Oncogenic signaling pathways activated by RON receptor tyrosine kinase. 1257 Jun 59

Signal transduction downstream HGF receptor (MET) activation involves multiple pathways that account for mitogenesis, motility and morphogenesis in a cell type-dependent fashion. MET receptor is aberrantly expressed in almost 100% of human osteosarcomas. We analyzed the effect of the MET receptor activation in five human osteosarcoma cell lines evaluating the levels of HGF-dependent activation of MAPK and PKB/AKT as biochemical readouts of mitogenic and invasive responses, respectively. All the cell lines tested expressed high levels of the MET proto-oncogene. Four cell lines showed activation of the MAPK cascade upon HGF stimulation, suggesting that this growth factor serves a common proliferative function in osteosarcomas. Two lines showed activation of PKB/AKT that is known to be involved in migration mediated by HGF receptor. Accordingly, cell lines where MAPK cascade was activated responded to HGF with increased proliferation, while induction and inhibition of PKB/AKT activity corresponded to acquisition or block of the invasive-motile response to HGF, respectively. Both the HGF dependent responses were reverted by the specific MET inhibitor K252a. These data show that HGF activates both the mitogen and motogen machinery in osteosarcoma cells and suggest that HGF might promote their malignant behavior by concomitant activation of different pathways and biological functions.
 ...
PMID:Role of the MET/HGF receptor in proliferation and invasive behavior of osteosarcoma. 1270 13

The Met receptor tyrosine kinase has been shown to be overexpressed or mutated in a variety of solid tumors and has, therefore, been identified as a good candidate for molecularly targeted therapy. Activation of the Met tyrosine kinase by the TPR gene was originally described in vitro through carcinogen-induced rearrangement. The TPR-MET fusion protein contains constitutively elevated Met tyrosine kinase activity and constitutes an ideal model to study the transforming activity of the Met kinase. We found, when introduced into an interleukin 3-dependent cell line, TPR-MET induces factor independence and constitutive tyrosine phosphorylation of several cellular proteins. One major tyrosine phosphorylated protein was identified as the TPR-MET oncoprotein itself. Inhibition of the Met kinase activity by the novel small molecule drug SU11274 [(3Z)-N-(3-chlorophenyl)-3-([3,5-dimethyl-4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrol-2-yl]methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide] led to time- and dose-dependent reduced cell growth. The inhibitor did not affect other tyrosine kinase oncoproteins, including BCR-ABL, TEL-JAK2, TEL-PDGFbetaR, or TEL-ABL. The Met inhibitor induced G(1) cell cycle arrest and apoptosis with increased Annexin V staining and caspase 3 activity. The autophosphorylation of the Met kinase was reduced on sites that have been shown previously to be important for activation of pathways involved in cell growth and survival, especially the phosphatidylinositol-3'-kinase and the Ras pathway. In particular, we found that the inhibitor blocked phosphorylation of AKT, GSK-3beta, and the pro-apoptotic transcription factor FKHR. The characterization of SU11274 as an effective inhibitor of Met tyrosine kinase activity illustrates the potential of targeting for Met therapeutic use in cancers associated with activated forms of this kinase.
 ...
PMID:A novel small molecule met inhibitor induces apoptosis in cells transformed by the oncogenic TPR-MET tyrosine kinase. 1450 Mar 82

Rhabdomyosarcomas (RMSs) are frequently characterized by bone marrow involvement. Recently, we reported that human RMS cells express the CXC chemokine receptor-4 (CXCR4) and postulated a role for the CXCR4 stromal-derived factor (SDF)-1 axis in the metastasis of RMS cells to bone marrow. Because RMS cells also express the tyrosine kinase receptor c-MET, the specific ligand hepatocyte growth factor (HGF) that is secreted in bone marrow and lymph node stroma, we hypothesized that the c-MET-HGF axis modulates the metastatic behavior of RMS cells as well. Supporting this concept is our observation that conditioned media harvested from expanded ex vivo human bone marrow fibroblasts chemoattracted RMS cells in an HGF- and SDF-1-dependent manner. Six human alveolar and three embryonal RMS cell lines were examined. We found that although HGF, similar to SDF-1, did not affect the proliferation of RMS cells, it induced in several of them: (a) locomotion; (b) stress fiber formation; (c) chemotaxis; (d) adhesion to human umbilical vein endothelial cells; (e) trans-Matrigel invasion and matrix metalloproteinase secretion; and (f) phosphorylation of mitogen-activated protein kinase p42/44 and AKT. Moreover HGF, but not SDF-1, increased the survival of RMS cells exposed to radio- and chemotherapy. We also found that the more aggressive alveolar RMS cells express higher levels of c-MET than embryonal RMS cell lines and "home/seed" better into bone marrow after i.v. injection into immunocompromised mice. Because we could not find any activating mutations in the kinase region of c-MET or any evidence for HGF autocrine stimulation, we suggest that the increased response of RMS cell lines depends on overexpression of functional c-MET. We conclude that HGF regulates the metastatic behavior of c-MET-positive RMS cells, directing them to the bone marrow and lymph nodes. Signaling from the c-MET receptor may also contribute to the resistance of RMS cells to conventional treatment modalities.
 ...
PMID:Both hepatocyte growth factor (HGF) and stromal-derived factor-1 regulate the metastatic behavior of human rhabdomyosarcoma cells, but only HGF enhances their resistance to radiochemotherapy. 1463 23

It has been demonstrated that exposure to cocaine increases cell death in the fetal CNS. To examine the molecular mechanisms of this effect, we employed mouse oligo microarrays followed by real-time reverse transcriptase-polymerase chain reaction (real-time RT-PCR) to compare expressions of apoptosis-related genes in the cerebral wall of 18-day-old (E18) fetuses from cocaine-treated (20 mg/kg cocaine, s.c., b.i.d., E8th-E18th) and drug-naive (saline, s.c.) mice. Out of approximately 400 relevant genes in the arrays, 53 showed alterations in expression in cocaine-exposed fetuses. Upregulation was observed in 35 proapoptotic and 8 antiapoptotic genes; 4 proapoptotic and 6 antiapoptotic genes were down-regulated. The affected genes encode a wide range of apoptosis-related proteins, including death receptors (NTF-R1, NTF-R2, DR3, DR5, LTbeta-R, GITR, P57 TR-1) and their adaptor and regulatory proteins (MASGE-D1, TRAF-2, SIVA, MET, FLIP, FAIM, IAP1, ATFA), members of transcription regulatory pathways (JNK, NF-kappaB, P53), members of BCL-2 family of proteins (BID, BAD, BAX, BIK, NIP21, NIP3, NIX, BCL-2), DNA damage sensor (PARP-1), caspases and their substrates and regulatory proteins (caspases 8, 4, 9, and 3, ACINUS, CIDE-A, CIDE-B, GAS2), mitochondrially released factors (cytochrome c, AIF, PRG3), specific endoplasmic reticulum- and oxidative stress-associated factors (BACH2, ABL1, ALG2, CHOP), members of cell survival AKT and HSP70 pathways (PIK3GA, PTEN, HSP70, BAG1, BAG2), and others. This suggests that cocaine affects survival of developing cerebral cells via multiple apoptosis-regulating mechanisms.
 ...
PMID:Cocaine-induced changes in the expression of apoptosis-related genes in the fetal mouse cerebral wall. 1568 Nov 17

RON is a member of the c-MET receptor tyrosine kinase family. Like c-MET, RON is expressed by a variety of epithelial-derived tumors and cancer cell lines and it is thought to play a functional role in tumorigenesis. To date, antagonists of RON activity have not been tested in vivo to validate RON as a potential cancer target. In this report, we used an antibody phage display library to generate IMC-41A10, a human immunoglobulin G1 (IgG1) antibody that binds with high affinity (ED50 = 0.15 nmol/L) to RON and effectively blocks interaction with its ligand, macrophage-stimulating protein (MSP; IC50 = 2 nmol/L). We found IMC-41A10 to be a potent inhibitor of receptor and downstream signaling, cell migration, and tumorigenesis. It antagonized MSP-induced phosphorylation of RON, mitogen-activated protein kinase (MAPK), and AKT in several cancer cell lines. In HT-29 colon, NCI-H292 lung, and BXPC-3 pancreatic cancer xenograft tumor models, IMC-41A10 inhibited tumor growth by 50% to 60% as a single agent, and in BXPC-3 xenografts, it led to tumor regressions when combined with Erbitux. Western blot analyses of HT-29 and NCI-H292 xenograft tumors treated with IMC-41A10 revealed a decrease in MAPK phosphorylation compared with control IgG-treated tumors, suggesting that inhibition of MAPK activity may be required for the antitumor activity of IMC-41A10. To our knowledge, this is the first demonstration that a RON antagonist and specifically an inhibitory antibody of RON negatively affects tumorigenesis. Another major contribution of this report is an extensive analysis of RON expression in approximately 100 cancer cell lines and approximately 300 patient tumor samples representing 10 major cancer types. Taken together, our results highlight the potential therapeutic usefulness of RON activity inhibition in human cancers.
 ...
PMID:Therapeutic implications of a human neutralizing antibody to the macrophage-stimulating protein receptor tyrosine kinase (RON), a c-MET family member. 1698 59

Hepatocyte growth factor (HGF) promotes cell growth and motility and also increases neovascularization. Multiple myeloma (MM) cells produce HGF, and the plasma concentration of HGF is significantly elevated in patients with clinically active MM, suggesting that HGF might play a role in the pathogenesis of MM. NK4, an antagonist of HGF, is structurally homologous to angiostatin, and our previous report showed that NK4 inhibited the proliferation of vascular endothelial cells induced by HGF stimulation. The purposes of this study were to elucidate the contribution of HGF to the growth of MM cells as well as to investigate the possibility of the therapeutic use of NK4. In vitro study showed that NK4 protein stabilized the growth of MM cell lines and regulated the activation of c-MET, ERK1/2, STAT3, and AKT-1. Recombinant adenovirus containing NK4 cDNA (AdCMV.NK4) was injected intramuscularly into Icr/scid mice bearing tumors derived from HGF-producing MM cells. AdCMV.NK4 significantly inhibited the growth of these tumors in vivo. Histologic examination revealed that AdCMV.NK4 induced apoptosis of MM cells, accompanied by a reduction in neovascularization in the tumors. Thus, NK4 inhibited the growth of MM cells via antiangiogenic as well as direct antitumor mechanisms. The molecular targeting of HGF by NK4 could be applied as a novel therapeutic approach to MM.
 ...
PMID:NK4, an antagonist of hepatocyte growth factor (HGF), inhibits growth of multiple myeloma cells: molecular targeting of angiogenic growth factor. 1717 34

The c-MET receptor can be overexpressed, amplified, or mutated in solid tumours including small cell lung cancer (SCLC). In c-MET-overexpressing SCLC cell line NCI-H69, hepatocyte growth factor (HGF) dramatically induced c-MET phosphorylation at phosphoepitopes pY1230/1234/1235 (catalytic tyrosine kinase), pY1003 (juxtamembrane), and also of paxillin at pY31 (CRKL-binding site). We utilised a global proteomics phosphoantibody array approach to identify further c-MET/HGF signal transduction intermediates in SCLC. Strong HGF induction of specific phosphorylation sites in phosphoproteins involved in c-MET/HGF signal transduction was detected, namely adducin-alpha [S724], adducin-gamma [S662], CREB [S133], ERK1 [T185/Y187], ERK1/2 [T202/Y204], ERK2 [T185/Y187], MAPKK (MEK) 1/2 [S221/S225], MAPKK (MEK) 3/6 [S189/S207], RB [S612], RB1 [S780], JNK [T183/Y185], STAT3 [S727], focal adhesion kinase (FAK) [Y576/S722/S910], p38alpha-MAPK [T180/Y182], and AKT1[S473] and [T308]. Conversely, inhibition of phosphorylation by HGF in protein kinase C (PKC), protein kinase R (PKR), and also CDK1 was identified. Phosphoantibody-based immunohistochemical analysis of SCLC tumour tissue and microarray established the role of c-MET in SCLC biology. This supports a role of c-MET activation in tumour invasive front in the tumour progression and invasion involving FAK and AKT downstream. The c-MET serves as an attractive therapeutic target in SCLC, as shown through small interfering RNA (siRNA) and selective prototype c-MET inhibitor SU11274, inhibiting the phosphorylation of c-MET itself and its downstream molecules such as AKT, S6 kinase, and ERK1/2. Investigation of mechanisms of invasion and, ultimately, metastasis in SCLC would be very useful with these signal transduction molecules.
 ...
PMID:Downstream signalling and specific inhibition of c-MET/HGF pathway in small cell lung cancer: implications for tumour invasion. 1766 9

In an attempt to find genes that may be of importance in malignant progression of papillary thyroid carcinoma (PTC) in the Middle East, which therefore can be targeted in cancer therapy, we screened and validated the global gene expression in PTC using cDNA expression arrays and immunohistochemistry (IHC) on tumour tissue microarrays. Twenty-nine PTC tissue specimens were compared with seven non-cancerous thyroid specimens by use of cDNA microarray. Results for selected genes were confirmed by quantitative real-time PCR. Protein expression of selected genes was further studied using a tissue microarray consisting of 536 PTCs and compared with histologically non-cancerous tissue samples. One hundred and ninety-six genes were overexpressed in PTC tissues relative to non-cancerous thyroid tissues. The genes that were up-regulated in PTC were involved in cell cycle regulation, cell signaling, and oncogenesis. Among these genes, c-MET was identified by immunohistochemical methods as a protein that is overexpressed in 37% of PTCs and was significantly associated with more aggressive behaviour, eg higher stage, nodal involvement, and tall cell variant (p value = 0.01, 0.01 and 0.04, respectively). In this study, 55% of the PTC cases expressed activated AKT (P-AKT), which suggests that activated AKT may play an important role in PTC tumourigenesis. The fact that most of the PTC cases that had activated AKT showed overexpression of c-MET (p = 0.027) leads us to hypothesize that c-MET may be an alternative mechanism of AKT activation in Middle Eastern PTCs. Finally, our data suggest that c-MET dysregulation is associated with aggressive behaviour and may serve as a molecular biomarker and potential therapeutic target in this disease.
 ...
PMID:Genome-wide expression analysis of Middle Eastern papillary thyroid cancer reveals c-MET as a novel target for cancer therapy. 1770 98

The CTTN gene (formerly designated EMS1), encodes cortactin, a key regulator of dynamic actin networks. Both CTTN and CCND1, the latter encoding the cell cycle regulator cyclin D1, reside at chromosomal locus 11q13, a region commonly amplified in breast cancers and head and neck squamous cell carcinoma (HNSCC). Previously, we identified a novel role for cortactin in cancer cells, whereby cortactin overexpression attenuated ligand-induced down-regulation of the epidermal growth factor (EGF) receptor (EGFR), leading to sustained signaling. However, how this affected growth factor-induced cellular responses was unclear. Here, by modulation of cortactin expression in a panel of HNSCC cell lines, we show that cortactin overexpression enhances serum- and EGF-stimulated proliferation under both anchorage-dependent and anchorage-independent conditions and also increases resistance to anoikis (detachment-induced apoptosis). These effects are associated with increased activation of extracellular signal-regulated kinase and/or AKT. Furthermore, we report that cortactin stabilizes the c-MET receptor tyrosine kinase and enhances hepatocyte growth factor-induced mitogenesis and cell scattering. Therefore, cortactin may modulate signaling by a broader range of receptors than originally proposed and thereby affect a variety of responses. Finally, we have determined that cortactin overexpression, either alone or in combination with cyclin D1 up-regulation, promotes resistance to the EGFR kinase inhibitor gefitinib. These findings indicate that cortactin may play multiple roles in progression of HNSCC and should be evaluated as a marker of prognosis, disease progression, and therapeutic responsiveness, particularly to EGFR-directed agents.
 ...
PMID:Aberrant expression of cortactin in head and neck squamous cell carcinoma cells is associated with enhanced cell proliferation and resistance to the epidermal growth factor receptor inhibitor gefitinib. 1790 38


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