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)

Aberrant methylation of tumor-suppressor gene promoter regions may play a causal role in the pre-neoplastic stage of cancer progression. In chronic myeloid leukemia, changes in the methylation status of the CpG-rich islands at several sites in the proximal ABL1 promoter (Pa) on the Philadelphia (Ph)-chromosome have been observed. It remains unclear if the Pa methylation precedes the translocation event (t9;22) that generates the Ph-chromosome or if Pa methylation is a stochastic event in a progenitor cell which will later acquire other mutations, namely t9;22. The present study was conducted to answer two questions: What is the methylation status of Pa in patients with Ph-negative myeloproliferative disorders (MPD)? Can the study of methylation in patients with Ph-negative MPD shed light on the initial events associated with the translocation? To probe CpG methylation, we used two methodologies; site-methylation-sensitive restriction enzyme assay and methylation-specific PCR analysis following modification of genomic DNA by bisulfite. Results showed that 22 of the 97 patients with Ph-negative MPD expressed BCR-ABL transcripts. Seven of the 97 patients possessed methylated Pa, but only 2 of them expressed BCR-ABL transcripts. In some of the patients, Pa methylation was a dynamic event. In conclusion, aberrant methylation in Ph-negative MPD could be an initial event triggering the occurrence of the t9;22 translocation and its clinical expression. These findings may shed light on the pathogenesis and progression of MPD.
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PMID:Detection of methylated ABL1 promoter in philadelphia-negative myeloproliferative disorders. 1266 92

Growth factor binding events to receptor tyrosine kinases result in activation of phosphatidylinositol 3-kinase (PI3K), and activated PI3K generates the membrane-bound second messengers phosphatidylinositol 3,4-diphosphate [PI(3,4)P2] and PI(3,4,5)P3, which mediate membrane translocation of the phosphoinositide-dependent kinase-1 (PDK1) and protein kinase B (PKB, also known as Akt). In addition to the kinase domain, PDK1 and PKB contain a pleckstrin homology (PH) domain that binds to the second messenger, resulting in the phosphorylation and activation of PKB by PDK1. Recent evidence indicates that constitutive activation of PKB contributes to cancer progression by promoting proliferation and increased cell survival. The indicating of PDK1 and PKB as primary targets for discovery of anticancer drugs, together with the observations that both PDK1 and PKB contain small-molecule regulatory binding sites that may be in proximity to the kinase active site, make PDK1 and PKB ideal targets for the development of new strategies to structure-based drug design. While X-ray structures have been reported for the kinase domains of PDK1 and PKB, no suitable crystals have been obtained for either PDK1 or PKB with their PH domains intact. In this regard, a novel structure-based strategy is proposed, which utilizes segmental isotopic labeling of the PH domain in combination with site-directed spin labeling of the kinase active site. Then, long-range distance restraints between the 15N-labeled backbone amide groups of the PH domain and the unpaired electron of the active site spin label can be determined from magnetic resonance studies of the enhancement effect that the paramagnetic spin label has on the nuclear relaxation rates of the amide protons. The determination of the structure and position of the PH domain with respect to the known X-ray structure of the kinase active site could be useful in the rational design of potent and selective inhibitors of PDK1 and PKB by 'linking' the free energies of binding of substrate (ATP) analogs with analogs of the inositol polar head group of the phospholipid second messenger. The combined use of X-ray crystallography, segmental isotopic and spin labeling, and magnetic resonance studies can be further extended to the study of other dynamic multidomain proteins and targets for structure-based drug design.
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PMID:PDK1 and PKB/Akt: ideal targets for development of new strategies to structure-based drug design. 1282 87

As its role in tumor progression emerges, the PI3K/PKB (Akt) pathway presents an appealing cancer therapeutic target. Recent studies have investigated the mechanisms underlying the tumor-promoting effects of this pathway. PKB triggers a network that positively regulates G1/S cell cycle progression through inactivation of GSK3-beta, leading to increased cyclin D1, and inhibition of Forkhead family transcription factors and the tumor suppressor tuberin (TSC2), leading to reduction of p27Kip1. The identification of p21Waf1/Cip1 and p27Kip1 as novel substrates of PKB provided new insights into mechanisms whereby hyperactivation of this lipid signaling pathway may lead to cell cycle deregulation in human cancers. The PI3K pathway may also play a key role in the G2/M transition and its constitutive activation may lead to defects in DNA damage checkpoint control.
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PMID:Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. 1285 86

It has been previously demonstrated that human carcinomas express interleukin-2 receptor (IL-2R) alpha, beta, and gamma chains. The beta and gamma chains of IL-2R have intermediate binding affinity for IL-2 and are responsible for the intracellular signaling cascades after IL-2 stimulation. IL-2Ralpha lacks the cytoplasmic domain, but is essential for increasing the IL-2-binding affinity of other receptors. Overexpression of IL-2Ralpha in tumor cells is associated with tumor progression and a poor patient prognosis. To define molecular mechanisms responsible for the effects associated with IL-2Ralpha expression, ex vivo experiments were performed with the squamous cell carcinoma head-and-neck cancer line, PCI-13, which was genetically engineered to overexpress the IL-2Ralpha chain. While IL-2Ralpha-overexpressing PCI-13 cells were capable of forming colonies in soft agar, PCI-13 cells transfected with the control vector or those expressing IL-2Rgamma did not. Consistently, IL-2Ralpha-expressing tumor cells proliferated more rapidly than the control or IL-2Rgamma+ cells, associated with increased levels of cyclins A and D1 and cyclin-dependent kinase (cdk(s)) 2 and 4 proteins. In addition, IL-2Ralpha-expressing cells were significantly more resistant to apoptosis induction by a tripeptidyl proteasome inhibitor (ALLN) and two chemotherapeutic drugs (VP-16 and taxol) than the control or IL-2Rgamma+ cells. Accompanying the drug resistance, high levels of anti-apoptotic Bcl-X(L) and Bcl-2 proteins were found in the mitochondria-containing fraction of IL-2Ralpha-expressing tumor cells. Treatment of IL-2Ralpha-expressing cells with a specific Janus kinase 3 (Jak3) inhibitor decreased expression of cyclin A, cyclin D1, Bcl-X(L), and Bcl-2 proteins. Finally, high levels of ubiquitinated proteins were detected in the proliferating IL-2Ralpha-expressing cells. Our data suggest that increased proliferation rates and decreased drug sensitivity of IL-2Ralpha-expressing tumor cells are responsible for the enhanced tumor aggressiveness and poor clinical prognosis of patients whose tumors express IL-2Ralpha.
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PMID:Overexpression of interleukin-2 receptor alpha in a human squamous cell carcinoma of the head and neck cell line is associated with increased proliferation, drug resistance, and transforming ability. 1285 47

Studies on signal transduction pathways have generated various promising molecular targets for therapeutic inhibition in cancer therapy. Receptor tyrosine kinases represent an important class of such therapeutic targets. c-Met is a receptor tyrosine kinase that has been shown to be overexpressed and/or mutated in a variety of malignancies. A number of c-Met activating mutations, many of which are located in the tyrosine kinase domain, have been detected in various solid tumors and have been implicated in invasion and metastasis of tumor cells. It is known that stimulation of c-Met via its natural ligand, hepatocyte growth factor (also known as scatter factor, HGF/SF) results in a plethora of biological and biochemical effects in the cell. Activation of c-Met signaling can lead to scattering, angiogenesis, proliferation, enhanced cell motility, invasion, and eventual metastasis. In this review, the role of c-Met dysregulation in tumor progression and metastasis is discussed in detail with particular emphasis on c-Met mutations. Moreover, we summarize current knowledge on various pathways of c-Met signal transduction, highlighting the central role in the cytoskeletal functions. In this summary is included recent data in our laboratory indicating that phosphorylation of focal adhesion proteins, such as paxillin, p125FAK, and PYK2, occurs in response to c-Met stimulation in lung cancer cells. Most importantly, current data on c-Met suggest that when mutated or overexpressed in malignant cells, c-Met would serve as an important therapeutic target.
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PMID:c-Met: structure, functions and potential for therapeutic inhibition. 1288 8

We have previously shown that the integrin beta6 is neo-expressed in invasive oral squamous cell carcinoma (SCC) and is correlated with oral tumor progression. However, the mechanism by which the integrin beta6 promotes oral tumor progression is not well understood. The purpose of the present study was to determine whether integrin beta6 signaling activates Fyn and thus promotes oral squamous cell carcinoma progression. We analyzed the integrin beta6 signaling complex and investigated the function of these signaling molecules in oral SCC cells. We found that, upon ligation of the integrin beta6 with fibronectin, beta6 complexed with Fyn and activated it. The activation of Fyn recruited and activated focal adhesion kinase to this complex. This complex was necessary to activate Shc and to couple beta6 signaling to the Raf-ERK/MAPK pathway. This pathway transcriptionally activated the matrix metalloproteinase-3 gene and promoted oral SCC cell proliferation and experimental metastasis in vivo. These findings indicate that integrin beta6 signaling activates Fyn and thus promotes oral cancer progression.
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PMID:Alphavbeta6-Fyn signaling promotes oral cancer progression. 1291 46

Ca2+ sensitivity of smooth muscle and nonmuscle myosin II reflects the ratio of activities of myosin light-chain kinase (MLCK) to myosin light-chain phosphatase (MLCP) and is a major, regulated determinant of numerous cellular processes. We conclude that the majority of phenotypes attributed to the monomeric G protein RhoA and mediated by its effector, Rho-kinase (ROK), reflect Ca2+ sensitization: inhibition of myosin II dephosphorylation in the presence of basal (Ca2+ dependent or independent) or increased MLCK activity. We outline the pathway from receptors through trimeric G proteins (Galphaq, Galpha12, Galpha13) to activation, by guanine nucleotide exchange factors (GEFs), from GDP. RhoA. GDI to GTP. RhoA and hence to ROK through a mechanism involving association of GEF, RhoA, and ROK in multimolecular complexes at the lipid cell membrane. Specific domains of GEFs interact with trimeric G proteins, and some GEFs are activated by Tyr kinases whose inhibition can inhibit Rho signaling. Inhibition of MLCP, directly by ROK or by phosphorylation of the phosphatase inhibitor CPI-17, increases phosphorylation of the myosin II regulatory light chain and thus the activity of smooth muscle and nonmuscle actomyosin ATPase and motility. We summarize relevant effects of p21-activated kinase, LIM-kinase, and focal adhesion kinase. Mechanisms of Ca2+ desensitization are outlined with emphasis on the antagonism between cGMP-activated kinase and the RhoA/ROK pathway. We suggest that the RhoA/ROK pathway is constitutively active in a number of organs under physiological conditions; its aberrations play major roles in several disease states, particularly impacting on Ca2+ sensitization of smooth muscle in hypertension and possibly asthma and on cancer neoangiogenesis and cancer progression. It is a potentially important therapeutic target and a subject for translational research.
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PMID:Ca2+ sensitivity of smooth muscle and nonmuscle myosin II: modulated by G proteins, kinases, and myosin phosphatase. 1450 7

AKT/PKB is a central signaling molecule related to stimulation of cell proliferation and inhibition of apoptosis. Perturbations of AKT expression and function play an important role in tumor development and progression. We wanted to determine (a) whether AKT is overexpressed in human prostatic tumors, (b) whether AKT expression is correlated with tumor grade, and (c) whether AKT expression correlates with clinicopathological parameters. AKT expression was investigated by immunohistochemistry in sections from 56 paraffin-embedded prostate specimens displaying benign prostatic tissue (BPT), prostatic intraepithelial neoplasia (PIN), and primary tumors graded 2-5 according to Gleason. The staining intensity for AKT was significantly more pronounced in tumors compared to BPT, with PIN ranging between BPT and carcinomas. Similarly, the fraction of AKT-positive cells was higher in tumors than in BPT. A score of AKT expression (calculated as product from intensity and fraction of positive cells) ranging from 0-6 was also significantly higher in tumors than in BPT. Furthermore, the intensity of AKT expression in tumors showed a positive correlation with high preoperative serum levels of prostate specific antigen (PSA >/= 10 ng/ml, p = 0.0325). These data show that AKT is upregulated in prostate cancer and that expression is correlated with tumor progression.
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PMID:Increase of AKT/PKB expression correlates with gleason pattern in human prostate cancer. 1452 Jul 10

Activation of the serine/threonine kinase Akt/PKB positively impacts on three cellular processes relevant to tumor progression: proliferation, survival, and cell size/growth. Using a three-dimensional culture model of MCF-10A mammary cells, we have examined how Akt influences the morphogenesis of polarized epithelial structures. Activation of a conditionally active variant of Akt elicits large, misshapen structures, which primarily arise from the combined effects of Akt on proliferation and cell size. Importantly, Akt activation amplifies proliferation during the early stages of morphogenesis, but cannot overcome signals suppressing proliferation in late-stage cultures. Akt also cooperates with oncoproteins such as cyclin D1 or HPV E7 to promote proliferation and morphogenesis in the absence of growth factors. Pharmacological inhibition of the Akt effector, mammalian target of rapamycin (mTOR), with rapamycin prevents the morphological disruption elicited by Akt activation, including its effect on cell size and number, and the cooperative effect of Akt on oncogene-driven proliferation, indicating that mTOR function is required for the multiple biological effects of Akt activation during morphogenesis.
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PMID:Akt activation disrupts mammary acinar architecture and enhances proliferation in an mTOR-dependent manner. 1456 91

Chemokines are implicated in tumor pathogenesis, although it is unclear whether they affect human cancer progression positively or negatively. We found that activation of the chemokine receptor CCR5 regulates p53 transcriptional activity in breast cancer cells through pertussis toxin-, JAK2-, and p38 mitogen-activated protein kinase-dependent mechanisms. CCR5 blockade significantly enhanced proliferation of xenografts from tumor cells bearing wild-type p53, but did not affect proliferation of tumor xenografts bearing a p53 mutation. In parallel, data obtained in a primary breast cancer clinical series showed that disease-free survival was shorter in individuals bearing the CCR5Delta32 allele than in CCR5 wild-type patients, but only for those whose tumors expressed wild-type p53. These findings suggest that CCR5 activity influences human breast cancer progression in a p53-dependent manner.
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PMID:CCR5 expression influences the progression of human breast cancer in a p53-dependent manner. 1459 37


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