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)

Several signaling pathways have been recognized in normal c-kit-mediated signal transduction following stem cell factor (SCF) stimulation including Janus kinase (JAK)/signal transducer and activator of transcription (STAT), mitogen-activated protein kinase (MAPK) and phosphoinositol 3-kinase (PI-3 K) pathways. In gastrointestinal stromal tumor (GIST), c-kit activation is considered to play a central role in its tumorigenesis. However, the signal transduction cascades specific for the SCF-independent c-kit activation in GIST remains to be elucidated. In this study, we examined for the expression of the activated form of STAT3 [phospho-STAT3 (tyr 705)] in eleven cases of GIST by immunohistochemistry. All GISTs had strong nuclear and variable cytoplasmic expression of phospho-STAT3 (tyr 705). Survival and proliferation of two established primary GIST cell lines with c-kit exon-11 mutations were then assessed for their response to inhibitors of c-kit (STI-571), JAK 2 (Tyrphostin AG490), MAPK kinase (PD98059) and PI-3 K(LY294002). GIST cells showed significant inhibition of proliferation and apoptosis when treated with STI571 or AG490 but not in cells treated with PD98059 or LY294002. Bcl-2 was expressed in all of the GIST cases (11 out of 11) and was down-regulated in the primary GIST cells following treatment with AG490. This study demonstrates that STAT3 is constitutively activated in GIST and JAK2 blockade leads to tumor growth inhibition and apoptosis indicating the involvement of the JAK/STAT signaling pathway in GIST cellular survival.
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PMID:Analysis of signal transducer and activator of transcription 3 (STAT3) in gastrointestinal stromal tumors. 1289

PTEN is a tumor suppressor frequently inactivated in brain, prostate, and uterine cancers that acts as a phosphatase on phosphatidylinositol-3,4,5-trisphosphate, antagonizing the activity of the phosphatidylinositol 3'-OH kinase. PTEN manifests its tumor suppressor function in most tumor cells by inducing G(1)-phase cell cycle arrest. To study the mechanism of cell cycle arrest, we established a tetracycline-inducible expression system for PTEN in cell lines lacking this gene. Expression of wild-type PTEN but not of mutant forms unable to dephosphorylate phosphoinositides reduced the expression of cyclin D1. Cyclin D1 reduction was accompanied by a marked decrease in endogenous retinoblastoma (Rb) protein phosphorylation on cyclin D/CDK4-specific sites, showing an early negative effect of PTEN on Rb inactivation. PTEN expression also prevented cyclin D1 from localizing to the nucleus during the G(1)- to S-phase cell cycle transition. The PTEN-induced localization defect and the cell growth arrest could be rescued by the expression of a nucleus-persistent mutant form of cyclin D1, indicating that an important effect of PTEN is at the level of nuclear availability of cyclin D1. Constitutively active Akt/PKB kinase counteracted the effect of PTEN on cyclin D1 translocation. The data are consistent with an oncogenesis model in which a lack of PTEN fuels the cell cycle by increasing the nuclear availability of cyclin D1 through the Akt/PKB pathway.
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PMID:PTEN induces cell cycle arrest by decreasing the level and nuclear localization of cyclin D1. 1291 36

The granulin-epithelin precursor, progranulin, PC-cell-derived growth factor or acrogranin, is a high molecular weight secreted mitogen. It is abundantly expressed in rapidly cycling epithelial cells, in the immune system and in neurons, such as cerebellar Purkinje cells. Progranulin contributes to tumorigenesis in diverse cancers, including breast cancer, clear cell renal carcinoma, invasive ovarian carcinoma and glioblastoma. It regulates the rate of epithelial cell division in responsive epithelial cells, and confers an invasive phenotype on these cells. It is involved in the wound response. During embryogenesis, progranulin accelerates blastocyst formation, and is a growth factor for trophectodermal cells. In the neonate, progranulin, regulates the hormone-dependent virilization of the hypothalamus. It activates phosphorylation of Shc, and p44/42 MAPK (mitogen activated protein kinase) in the ERK (extracellular regulated kinase) signaling pathway; PI3K (phosophatidyl inositol-3-kinase), AKT/protein kinase B, and p70S6kinase in the phosophatidyl inositol-3-kinase pathway; and focal adhesion kinase in the adhesion/motility pathway. The signaling properties of progranulin are apparently similar to those of classic growth factors, but the functional properties of progranulin distinguish it from these molecules. Deleting the insulin-like growth factor I receptor from murine embryonic fibroblasts blocks proliferation in response to all classic growth factors, such as epidermal growth factor, or platelet-derived growth factor, whereas progranulin retains mitotic activity on these cells. The defined biological actions of progranulin probably represent a small fraction of its overall functions. Transcriptome analyses show that the progranulin gene is induced in numerous situations that vary from obesity to the transcriptional response of cells to antineoplastic drugs. Here, the biological roles of progranulin will be reviewed, with an emphasis on cancer and cell proliferation.
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PMID:Progranulin (granulin-epithelin precursor, PC-cell derived growth factor, acrogranin) in proliferation and tumorigenesis. 1297 94

Pancreatic endocrine tumours (PETs) occur sporadically or are inherited as part of the multiple endocrine neoplasia type-1 syndrome. Little is known about the molecular events leading to these tumours. Cyclin D1, a key regulator of the G1/S transition of the cell cycle, is overexpressed in a variety of human cancers as well as certain endocrine tumours. We hypothesized that similar to other endocrine tumours, cyclin D1 is overexpressed in human sporadic PETs. Cyclin D1 protein overexpression was found in 20 of 31 PETs (65%) when compared with normal pancreatic tIssue. Furthermore, Northern blot analysis suggests that cyclin D1 up-regulation occurs at the post-transcriptional level in some PETs. Because the key cell growth signalling pathways p42/p44/ERK (extracellular signal-regulated kinase), p38/MAPK (mitogen-activated protein kinase), and Akt/PKB (protein kinase B) can regulate cyclin D1 protein expression in other cell types, pancreatic endocrine tumours were analysed with phospho-specific antibodies against the active forms of these proteins to elucidate a tIssue-specific regulatory mechanism of cyclin D1 in PETs. We found frequent activation of the p38/MAPK and Akt pathways, but down-regulation of the ERK pathway, in cyclin D1 overexpressing PETs. This study demonstrates that cyclin D1 overexpression is associated with human sporadic PET tumorigenesis, and suggests that this up-regulation may occur at the post-transcriptional level. These findings will direct future studies of PETs towards cell cycle dysregulation and the identification of key growth factor pathways involved in the formation of these tumours.
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PMID:Frequent overexpression of cyclin D1 in sporadic pancreatic endocrine tumours. 1452 67

Chronic myelogenous leukemia (CML) is characterized by a t(9;22) translocation resulting in expression of BCR-ABL fusion oncoproteins which are unique to the leukemic cells, necessary for oncogenesis, and potentially immunogenic. We have previously shown that human dendritic cells transduced with an adeno-associated virus vector encoding the fusion region of the b3a2 splice variant (p210(b3a2)) of the BCR-ABL oncoprotein elicit specific T-cell responses in vitro. Two cytotoxic T lymphocyte (CTL) clones generated in this fashion displayed restriction with previously unreported HLA alleles. The first, T1/B9, was CD4(+) and restricted by DRB5*0101 (autologous) or DRB1*1101 (allogeneic). The minimum cytotoxic epitope (MCE) binding to DRB5*0101 for this clone was identified as FKQSSKALQ, overlapping the p210(b3a2) fusion point (boldface). The MCE of DRB1*1101 for this clone differed from DRB5*0101, but also included the fusion point. The clonality of CTL T1/B9 was verified by analyses of TCRalpha/beta chain usage and DNA sequence analyses. To our knowledge, this is the first description of a single clone recognizing both DRB5*0101 and DRB1*1101. The other CTL clone, T1/33, was CD8+ and recognized HLA-B*3501 or B*3503 complexed with an MCE, RPVASDFEP, derived from the c-abl sequence in proximity to the p210(b3a2) fusion point. K562 cells transfected with plasmids encoding HLA-DRA + B5*0101, B*3501, or B*3503 but not controls expressing DRA + DRB1*1501 were lysed by cognate CTL clones, confirming that DRB5*0101 and B*3501/3 could present p210(b3a2) joining region epitopes via endogenous processing. The identification of three additional HLA alleles (DRB5*0101, B*3501, and B*3503) presenting the p210(b3a2) fusion-region antigen will broaden the application of vaccine strategies for targeting CML cells. The findings of single CTL clones cross-recognizing autologous (DRB5*0101 or B*3501) and allogeneic (DRB1*1101 or B*3503) HLA alleles presenting BCR-ABL fusion-region epitopes implies the potential separation of graft-versus-leukemia from graft-versus-host effects.
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PMID:Identification of new MHC-restriction elements for presentation of the p210(BCR-ABL) fusion region to human cytotoxic T lymphocytes. 1456 82

Interleukin-6 (IL-6) is a growth and antiapoptotic factor for human myeloma cells. The autocrine loop and increased expression of the growth factor receptors have been postulated as the mechanisms of tumorigenesis. Here we show that IL-6 stimulation induced the phosphorylation of insulin-like growth factor-I (IGF-I) receptors in a human myeloma cell line, NOP2, highly expressing IL-6 receptor alpha (IL-6R alpha) and in the IL-6R alpha-transfected U266 cell line. IL-6-dependent complex formation of IL-6R alpha with IGF-I receptor beta was found in NOP2 where IL-6R alpha colocalized with IGF-I receptors at lipid rafts. Moreover, the IL-6-induced phosphorylation of IGF-I receptor beta was not blocked by a Janus kinase 2 (Jak2) inhibitor. In addition to the activation of the signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2, IL-6 stimulation led to the activation of Akt, presumably following the phosphorylation of IGF-I receptors. Thus, our results suggest that in NOP2, IL-6R alpha and IGF-I receptors exist on the plasma membrane in close proximity, facilitating the efficient assembly of 2 receptors in response to IL-6. The synergistic effects of highly expressed IL-6R alpha on IGF-I receptor-mediated signals provide a novel insight into the Jak-independent IL-6 signaling mechanism of receptor cross-talk in human myeloma cells.
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PMID:Receptor synergy of interleukin-6 (IL-6) and insulin-like growth factor-I in myeloma cells that highly express IL-6 receptor alpha [corrected]. 1459 26

Phosphoinositide 3-kinase (PI 3-K) is implicated in a wide array of biological and pathophysiological responses, including tumorigenesis, invasion and metastasis, therefore specific inhibitors of the kinase may prove useful in cancer therapy. We propose that specific inositol polyphosphates have the potential to antagonize the activation of PI 3-K pathways by competing with the binding of PtdIns(3,4,5)P3 to pleckstrin homology (PH) domains. Here we show that Ins(1,3,4,5,6)P5 inhibits the serine phosphorylation and the kinase activity of Akt/PKB. As a consequence of this inhibition, Ins(1,3,4,5,6)P5 induces apoptosis in ovarian, lung and breast cancer cells. Overexpression of constitutively active Akt protects SKBR-3 cells from Ins(1,3,4,5,6)P5-induced apoptosis. Furthermore, Ins(1,3,4,5,6)P5 enhances the proapoptotic effect of cisplatin and etoposide in ovarian and lung cancer cells, respectively. These results support a role for Ins(1,3,4,5,6)P5 as a specific inhibitor of the PI 3-K/Akt signalling pathway, that may sensitize cancer cells to the action of commonly used anticancer drugs.
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PMID:Inositol pentakisphosphate promotes apoptosis through the PI 3-K/Akt pathway. 1475 53

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

Ovarian carcinoma (OC) is a leading cause of death among women throughout the world. A number of cancer-associated genes have been shown to be inactivated by hypermethylation of CpG islands during tumorigenesis. We tested the hypothesis that methylation status of MGMT, CDH1, RAR-beta and SYK could be important in the ovarian tumorigenic process and can lead to the gene(s) inactivation. Therefore, we assessed the promoter hypermethylation of MGMT, CDH1, RAR-beta and SYK in 43 ovarian granulosa cell tumours (GCTs) (adult type) using methylation-specific PCR. These tumours are relatively rare, accounting for approximately 3% of all ovarian cancers. Hypermethylation of MGMT (in 14 tumours), CDH1 (in nine tumours), RAR-beta (in eight tumours) and SYK (in seven tumours) have been found. Selective loss of RAR-beta and RAR-beta2 mRNA has been found in seven patients, while that of MGMT and SYK in three patients who also show aberrant methylation in promoter region of RAR-beta in addition to MGMT, SYK and CDH1 genes. Promoter CpG hypermethylation may be an alternative to mutation(s) to inactivate tumour suppressor genes such as MGMT, CDH1, RAR-beta and SYK, and this can also be an early event in the pathogenesis of OCs. Moreover, hypermethylation of the MGMT and CDH1, MGMT and RAR-beta and CDH1 and RAR-beta promoters occurred concordantly (P< 0.001, 0.0421 and 0.0005 respectively; Fischer's exact test). In addition to this, monosomy 22 and trisomy 14 have also been found in 10 tumours. It is clear from the results that hypermethylation of the promoter region of these tumour suppressor genes, monosomy 22 and trisomy 14, may be critical steps in the tumorigenesis, which consequently play a permissive role for tumour aggressiveness. All these events might play an important role in the early clinical diagnosis of the disease. Our results, therefore, suggest a potential role for epigenetic modification of these critical tumour suppressor genes in pathways relevant to the transformation and differentiation of rare type of ovarian cancer (GCTs).
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PMID:Promoter hypermethylation of MGMT, CDH1, RAR-beta and SYK tumour suppressor genes in granulosa cell tumours (GCTs) of ovarian origin. 1497 Aug 67

Prolactin is an ancient hormone, with different functions in many species. The binding of prolactin to its receptor, a member of the cytokine receptor superfamily, results in the activation of different intracellular signaling pathways, such as JAK2/STAT5, MAP kinase, and PI3K/AKT. How prolactin elicits so many different biological responses remains unclear. Recently, microarray technology has been applied to identify prolactin target genes in different systems. Here, we attempt to summarize and compare the available data. Our comparison of the genes reported to be transcriptionally regulated by prolactin indicates that there are few genes in common between the different tissues. Among the organs studied, mammary and prostate glands displayed the largest number of overlaps in putative prolactin target genes. Some of the candidates have been implicated in tumorigenesis. The relevance and validation of microarray data, as well as comparison of the results obtained by different groups, will be discussed.
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PMID:Using gene expression arrays to elucidate transcriptional profiles underlying prolactin function. 1497 73


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