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)

The role of vascular permeability in the preferential accumulation of photosensitizers in tumor tissue was investigated. Two murine tumors [experimental mammary tumor carcinoma (EMT-6) and methylcholanthrene-induced rhabdomyosarcoma (M1S)] and a human bladder carcinoma (EJ) were grown s.c. on the flank in athymic nude mice and analyzed for in vivo vessel permeability, vascular permeability factor (VPF) secretion, and accumulation of the photosensitizer, chloroaluminum sulfonated phthalocyanine. In vivo tumor vessel permeability and vascular volume were quantitated by measuring Evans blue extravasation and accumulation of a high molecular weight fluoresceinated dextran, respectively. VPF was isolated from serum-free tumor cell conditioned medium using heparin-Sepharose affinity chromatography. Dot and Western blots stained with anti-VPF antiserum positively identified VPF in samples from each tumor. Chloroaluminum sulfonated phthalocyanine pharmacokinetics in tumor-bearing mice were measured using a fiber-based spectrofluorometer. In vivo vessel permeability was found to be greatest in M1S tumors, next in EMT-6 tumors and finally in EJ tumors. Consistent with in vivo data, M1S and EMT-6 tumor cells in culture secrete significantly more VPF than EJ tumor cells. Chloroaluminum sulfonated phthalocyanine accumulation was approximately 2 times greater in M1S and EMT-6 tumors compared to EJ tumors. Our data present evidence that photosensitizer accumulation can be correlated to in vivo tumor vessel permeability and VPF secretion of that tumor. Taken together, the data support the hypothesis that vascular permeability differences among tumors play a significant role in the uptake and retention of photodynamic agents.
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PMID:Tumor-secreted vascular permeability factor/vascular endothelial growth factor influences photosensitizer uptake. 841 39

During the past two decades we have witnessed the identification of an expanding list of immunohistochemical and molecular markers linked to histopathologically defined subtypes of tumors. These markers offer new insights and approaches to the classification of tumors with important prognostic and/or therapeutic implications. We review the potentially diagnostic immunohistochemical and molecular markers of soft tissue tumors (STTs). The immunohistochemical markers reviewed include vimentin, cytokeratin, desmin, HHF35, S100, myoD1, alpha1-antitrypsin, vascular markers (factor VIII, CD31, CD34), MIC2, and others. The potentially diagnostic chromosomal translocations and associated genes identified in STT include Ewing's/PNET t(11;22)(q24;q12)(FLI1;EWS), t(21;22)(q22;q12)(ERG; EWS); t(7;22)(p22;q12)(ETV1;EWS); desmoplastic small round cell tumor t(11;22)(p13;q12)(WT1;EWS); extraskeletal myxoid chondrosarcoma t(9;22)(q22;q12) (TEC(CHN);EWS); malignant ectomesenchymoma t(11;22)(q24;q12)(FLI1;EWS); alveolar rhabdomyosarcoma t(2;13)(q35;q14)(PAX-3;FKHR); t(1;13) (p36;q14)(PAX-7;FKHR); myxoid and round cell liposarcoma t(12;16)(q13;p11)(CHOP;TLS(FUS)); synovial sarcoma t(X;18)(p11;q11)(SSX1&2;SYT), and others. The nature, utility, and limitations of these markers in diagnostic settings are explored.
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PMID:Immunohistochemical and molecular genetic approaches to soft tissue tumor diagnosis: a primer. 934 17

We have previously demonstrated that vascular endothelial growth factor-165 (VEGF), a tumor-secreted angiogenic factor, can acutely and chronically induce fenestrations in microvascular endothelium (Cancer Res 1997, 57:765-772). Because the morphology and function of microvascular endothelium differs from tissue to tissue, we undertook studies to examine whether the neovasculature in tumors also differed depending upon tumor location. Four tumor types implanted in the brain or subcutis in nude mice were studied: a murine rhabdomyosarcoma (M1S), a murine mammary carcinoma (EMT), and two human glioblastomas (U87 and U251). In addition, we studied Chinese hamster ovary cells stably transfected with human VEGF165. As previously reported, tumors grown in the subcutaneous space had a microvasculature that was fenestrated and had open endothelial gaps. The identical tumors when grown in the brain also had fenestrated endothelium and vessels with open endothelial gaps, but they were drastically reduced in occurrence. Open endothelial gaps were not seen in all tumors implanted in the brain (EMT and M1S), although fenestrated endothelium was always seen. VEGF and VEGF receptors were measured in tumors from both locations by immunoblotting and competitive polymerase chain reaction, respectively. VEGF amount was not significantly different between the tumor locations. Interestingly, total tumor vascular mRNA expression of both Flk-1 and Flt-1 was greater in tumor vessels derived from the brain compared with tumor vessels derived from subcutaneous tissues. These results demonstrate that the host microvascular environment determines the morphology and function of the tumor vasculature and that endothelia from different tissues vary in their ability to express the VEGF receptors given identical stimuli.
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PMID:Host microvasculature influence on tumor vascular morphology and endothelial gene expression. 977 55

Protein kinase B lies "downstream" of phosphatidylinositide (PtdIns) 3-kinase and is thought to mediate many of the intracellular actions of insulin and other growth factors. Here we show that FKHR, a human homologue of the DAF16 transcription factor in Caenorhabditis elegans, is rapidly phosphorylated by human protein kinase Balpha (PKBalpha) at Thr-24, Ser-256, and Ser-319 in vitro and at a much faster rate than BAD, which is thought to be a physiological substrate for PKB. The same three sites, which all lie in the canonical PKB consensus sequences (Arg-Xaa-Arg-Xaa-Xaa-(Ser/Thr)), became phosphorylated when FKHR was cotransfected with either PKB or PDK1 (an upstream activator of PKB). All three residues became phosphorylated when 293 cells were stimulated with insulin-like growth factor 1 (IGF-1). The IGF-1-induced phosphorylation was abolished by the PtdIns 3-kinase inhibitor wortmannin but not by PD 98059 (an inhibitor of the mitogen-activated protein kinase cascade) or by rapamycin. These results indicate that FKHR is a physiological substrate of PKB and that it may mediate some of the physiological effects of PKB on gene expression. DAF16 is known to be a component of a signaling pathway that has been partially dissected genetically and includes homologues of the insulin/IGF-1 receptor, PtdIns 3-kinase and PKB. The conservation of Thr-24, Ser-256, and Ser-319 and the sequences surrounding them in DAF16 therefore suggests that DAF16 is also a direct substrate for PKB in C. elegans.
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PMID:Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B. 1035 75

The STAT multigene family of transcriptional regulators conveys signals from several cytokines and growth factors upon phosphorylation by janus kinases (JAK). Activation of STAT5 is typically mediated by JAK2, but more recent data indicate a direct activation by the insulin receptor kinase. STAT5 exists in two closely homologous isoforms, STAT5a and b. We here describe the selective tyrosine phosphorylation of STAT5b in Kym-1 cells in response to insulin. Blocking insulin signalling by HNMPA-(AM)(3), an insulin receptor kinase inhibitor, resulted in the loss of insulin-induced STAT5b tyrosine phosphorylation, whereas the inhibition of JAK2 by the JAK selective inhibitor tyrphostin AG490 had no effect. By contrast, in the same cells, IFNgamma-induced STAT5b activation was JAK2-dependent, indicating that this signal pathway is functional in Kym-1 cells. We conclude from this rhabdomyosarcoma model that STAT5b, but not STAT5a is a direct target of the insulin receptor kinase.
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PMID:Insulin selectively activates STAT5b, but not STAT5a, via a JAK2-independent signalling pathway in Kym-1 rhabdomyosarcoma cells. 1061 97

The potential link between aging and insulin signaling has attracted substantial attention since several decades ago, on the basis of evidence including age-related increase in incidence of insulin resistance, insulin resistance and type 2 diabetes in accelerated aging syndromes and lifespan extension by caloric restriction in rodents. In addition, the intensive investigations in C. elegans in the 1990's, which have identified insulin signaling components including daf-2, age-1 and daf-16 as the genes whose mutations lead to lifespan extension, shed new light on molecular mechanisms underlying aging. As suggested by the genetic studies in C. elegans, it was recently demonstrated that FKHR, FKHRL1 and AFX, which are mammalian homologues of daf-16 forkhead transcription factor, function downstream of insulin signaling and Akt/PKB under cellular conditions. However, it is an open question whether insulin signaling components, including forkhead transcription factors, play a critical role in aging and longevity in mammals as well as in C. elegans. Increasing evidence concerning C. elegans indicates that augmented resistance to stress, in particular, that to oxidative stress is involved in lifespan extension by genetic mutations of insulin signaling components. The intriguing finding that signals from the reproductive system regulate lifespan by modulating the activities of insulin signal transduction pathway in C. elegans suggests a possibility of co-evolution of reproduction and aging. The significance of studies on C. elegans with regard to human aging is discussed.
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PMID:[Insulin receptor and aging]. 1068 93

Adhesion to extracellular matrix (ECM) induces intracellular signals that modulate cell proliferation, survival and differentiation. To study signalling events triggered by cell-ECM interactions in vivo we used transgenic mice exhibiting reduced mammary epithelial cell proliferation and increased apoptosis rates during the growth phase in pregnancy and lactation due to expression of a beta1-integrin dominant-negative mutant in the mammary gland epithelium. Here we show that ERK and JNK MAPKs were markedly less activated in lactating transgenic glands thereby accounting for the growth defects. The FAK pathway was not affected suggesting a mechanism of activation additional to the ECM signal. On the contrary, the significant decrease of Shc phosphorylation, Grb2 recruitment and the reduced phosphorylation level of Akt Thr308 and Akt substrates FKHR and Bad detected in transgenic glands show that activation of the Shc and the Akt pathways require intact cell-ECM interactions. These results provide an insight into the mechanisms of growth control by integrin-mediated adhesion that operate in vivo.
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PMID:Growth defects induced by perturbation of beta1-integrin function in the mammary gland epithelium result from a lack of MAPK activation via the Shc and Akt pathways. 1137 36

Activation of the G-protein-coupled receptor for glucose-dependent insulinotropic polypeptide facilitates insulin-release from pancreatic beta-cells. In the present study, we examined whether glucose-dependent insulinotropic polypeptide also acts as a growth factor for the beta-cell line INS-1. Here, we show that glucose-dependent insulinotropic polypeptide induced cellular proliferation synergistically with glucose between 2.5 mM and 15 mM by pleiotropic activation of signaling pathways. Glucose-dependent insulinotropic polypeptide stimulated the signaling modules of PKA/cAMP regulatory element binder, MAPK, and PI3K/protein kinase B in a glucose- and dose-dependent manner. Janus kinase 2 and signal transducer and activators of transcription 5/6 pathways were not stimulated by glucose-dependent insulinotropic polypeptide. Activation of PI3K by glucose-dependent insulinotropic polypeptide and glucose was associated with insulin receptor substrate isoforms insulin receptor substrate-2 and growth factor bound-2 associated binder-1 and PI3K isoforms p85alpha, p110alpha, p110beta, and p110gamma. Downstream of PI3K, glucose-dependent insulinotropic polypeptide-stimulated protein kinase Balpha and protein kinase Bbeta isoforms and phosphorylated glycogen synthase kinase-3, forkhead transcription factor FKHR, and p70S6K. These data indicate that glucose-dependent insulinotropic polypeptide functions synergistically with glucose as a pleiotropic growth factor for insulin-producing beta-cells, which may play a role for metabolic adaptations of insulin-producing cells during type II diabetes.
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PMID:Glucose-dependent insulinotropic polypeptide is a growth factor for beta (INS-1) cells by pleiotropic signaling. 1151 6

C. elegans insulin-like signaling regulates metabolism, development, and life span. This signaling pathway negatively regulates the activity of the forkhead transcription factor DAF-16. daf-16 encodes multiple isoforms that are expressed in distinct tissue types and are probable orthologs of human FKHRL1, FKHR, and AFX. We show that human FKHRL1 can partially replace DAF-16, proving the orthology. In mammalian cells, insulin and insulin-like growth factor signaling activate AKT/PKB kinase to negatively regulate the nuclear localization of DAF-16 homologs (reviewed in ). We show that the absence of AKT consensus sites on DAF-16 is sufficient to cause dauer arrest in daf-2(+) animals, proving that daf-16 is the major output of insulin signaling in C. elegans. FKHR, FKRHL1, and AFX may similarly be the major outputs of mammalian insulin signaling. daf-2 insulin signaling, via AKT kinases, negatively regulates DAF-16 by controlling its nuclear localization. Surprisingly, we find that daf-7 TGF-beta signaling also regulates DAF-16 nuclear localization specifically at the time when the animal makes the commitment between diapause and reproductive development. daf-16 function is supported by the combined action of two distinct promoter/enhancer elements, whereas the coding sequences of two major DAF-16 isoforms are interchangeable. Together, these observations suggest that the combined effects of transcriptional and posttranslational regulation of daf-16 transduce insulin-like signals in C. elegans and perhaps more generally.
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PMID:Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway. 1174 21

Little is known regarding hepatic insulin-like growth factor-1 IGF-I signaling with aging despite the observation that other tissues demonstrate resistance to IGF-I with aging and declines in liver mass accompany aging. Our aim was to determine if the IGF-I-induced signaling process changes with aging. Young (5 months) and old (24 months) C57BL/6 mice hepatic tissues and blood samples were taken 20 min after an intraperitoneal injection of desIGF-I. Age had no significant effect on plasma glucose, insulin and total IGF-I levels. IRS-1 protein was significantly decreased (33%) with aging. Basal phosphorylation of IRS-1, PKB and ERK were unaffected whereas basal phosphorylation of CREB and FKHR were significantly increased (37 and 33%, respectively) with aging. desIGF-I caused a significant decrease in plasma glucose concentrations in both young (53%) and old (44%) mice. desIGF-I administration significantly increased the phosphorylation of IRS-1 in both young (104%) and old (89%) hepatic tissues. Similarly, the phosphorylation of PKB was dramatically enhanced in both young (527%) and old (350%) hepatic tissues after desIGF-I stimulation. By contrast, desIGF-I administration had no significant effects on the phosphorylation of ERK and phosphorylation of transcription factors CREB and FKHR in both young and old hepatic tissues. These data suggest that aging dose not impair IGF-I signaling in hepatic tissues.
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PMID:Effects of aging on hepatic IGF-I signaling. 1185 24


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