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)

Activated pp60c-src has been implicated in a number of human malignancies including colon carcinoma and breast adenocarcinoma. Association of the src SH2 domain with tyrosine-phosphorylated proteins plays a role in src-mediated signal transduction. Inhibitors of src SH2 domain-phosphoprotein interactions are, thus, of great interest in defining the role(s) of src in signal transduction pathways. To facilitate such studies, an enzyme-linked immunosorbent assay (ELISA) was developed to detect inhibitors of src SH2-phosphoprotein interactions. This assay measures inhibition of binding of a fusion construct (glutathione S-transferase src SH3-SH2) with autophosphorylated epidermal growth factor receptor tyrosine kinase domain. Activities of phosphopeptide segments derived from potential src SH2 cognate phosphoprotein partners were determined, with the focal adhesion kinase-derived segment VSETDDY*AEIIDE yielding the highest inhibitory activity. Structure activity studies starting from acetyl (Ac)-Y*EEIE have identified Ac-Y*Y*Y*IE as the most active compound screened in the ELISA. This compound is at least 20-fold more active than the parent peptide Ac-Y*EEIE. A high resolution (2 A) crystal structure of human src SH2 complexed with Ac-Y*EEIE was obtained and provided a useful framework for understanding the structure-activity relationships. Additionally, Ac-Y*EEIE was able to block interactions between src and its cellular phosphoprotein partners in vanadate-treated cell lysates from MDA-MB-468 breast carcinoma cells. However, it is unable to abrogate proliferation of MDA-MB-468 cells in culture, presumably because of poor cell penetration and/or lability of the phosphate group on tyrosine.
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PMID:Peptide inhibitors of src SH3-SH2-phosphoprotein interactions. 752 93

The interaction of cells with components of the extracellular matrix through their integrin receptors results in the stimulation of tyrosine phosphorylation of several proteins, suggesting that these receptors play a key role in signal transduction. Here we report that antibody-mediated ligation and clustering of alpha 3 beta 1 and alpha 6 beta 1/alpha 6 beta 4 integrins resulted in the stimulation of tyrosine phosphorylation of proteins that are specific for each heterodimer. Thus, ligation and clustering of the alpha 3 beta 1 integrin on human prostate carcinoma cells (PC-3) and human umbilical vein endothelial cells (HUVEC) with anti-alpha 3 antibodies resulted in the stimulation of tyrosine phosphorylation of a 55 kDa protein. In contrast, ligation and clustering of the alpha 6 beta 1 integrin on these cells with anti-alpha 6 antibody resulted in the dramatic stimulation of tyrosine phosphorylation of a 90 kDa protein in addition to a 52 kDa protein, and ligation and clustering of alpha 5 beta 1 on HUVEC did not result in the apparent stimulation of tyrosine phosphorylation of any proteins. Clustering with anti-beta 1 antibodies triggered the tyrosine phosphorylation of all of these proteins, whereas ligation and clustering of PC-3 cells with an anti-beta 4 antibody resulted in the tyrosine phosphorylation of a distinct 62 kDa protein. Since the PC-3 cells express both alpha 6 beta 1 and alpha 6 beta 4, these data suggest that these two receptors can transduce distinct signals. All of the phosphorylations could be inhibited by treating the cells with Genistein, a tyrosine kinase inhibitor. Antibody-mediated ligation and clustering of integrins on the two types of cells did not result in the stimulation of tyrosine phosphorylation of pp125 focal adhesion kinase, although this was observed upon cell attachment and spreading on fibronectin, laminin and anti-alpha 3 monoclonal antibody. Collectively, these data demonstrate that cross-linking of different integrin heterodimers can stimulate tyrosine kinase activities, leading to the phosphorylation of distinct proteins, which are also different from those observed when cells are allowed to spread on a matrix.
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PMID:Stimulation of tyrosine phosphorylation of distinct proteins in response to antibody-mediated ligation and clustering of alpha 3 and alpha 6 integrins. 762 2

Paracrine motogenic cytokines secreted by normal cells can stimulate metastatic cell invasion. For example, human fibroblasts secrete hepatocyte growth factor/scatter factor (HGF/SF), which stimulates paracrine migration of epithelial and certain carcinoma cells, and migration-stimulating factor (MSF), which stimulates autocrine migration of fibroblasts from certain breast carcinomas. We found that human peri-tumoral and lung fibroblasts secrete motility-stimulating activity for several recently established human sarcoma cell strains. Motility of lung metastasis-derived SYN-I sarcoma cells was preferentially stimulated by human lung and peri-tumoral fibroblast motility-stimulating factors (FMSFs). FMSFs were non-dialyzable, susceptible to trypsin and sensitive to dithiothreitol. Cycloheximide inhibited accumulation of FMSF activity in conditioned medium; however, addition of cycloheximide to the migration assay did not significantly affect motility-stimulating activity. Purified HGF/SF, rabbit anti-hHGF and RT-PCR analysis of peri-tumoral and lung fibroblast HGF/SF mRNA expression indicated that FMSF activity was unrelated to HGF/SF. Partial purification of FMSF by gel exclusion chromatography revealed several peaks of activity, suggesting multiple FMSF molecules or complexes. Since human soft tissue sarcomas have a distinctive hematogenous metastatic pattern (predominantly lung), FMSF may play a role in this process independent of HGF/SF.
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PMID:Human peri-tumoral and lung fibroblasts produce paracrine motility factors for recently established human sarcoma cell strains. 766 30

To analyze the role of various elements of the adhesion system in the organization of the normal mammary gland and in breast carcinoma, we have studied simultaneously the expression of integrins, E- and P-cadherins, and cytoplasmic constituents of adherens junctions. In the normal gland, E-cadherin and alpha-catenin are present in luminal epithelial and myoepithelial cells, whereas integrins are more abundant in acinar epithelial and in myoepithelial cells. We demonstrate here that, in addition, myoepithelial cells express much more vinculin and alpha-actinin than luminal epithelial cells, whereas talin and focal adhesion kinase (pp125FAK) are restricted to the basal cell layer. In invasive carcinoma, E-cadherin is usually present although often in reduced amount; different integrin subunits are expressed either by a fraction or by all of the cells or are absent. However, the cytoplasmic components of adherens junctions, such as alpha-catenin, vinculin, alpha-actinin, talin, and pp125FAK, are expressed at low levels or cannot be detected in the carcinoma cells. Our data suggest that 1), in the normal mammary gland, the myoepithelial cells, being particularly rich in integrins and cytoplasmic components of the adherens junctions, play an important role in the maintenance of tissue integrity; 2), in invasive carcinoma, cell aggregates may be maintained due to varying levels of expression of E-cadherin and/or integrins; and 3), interaction of the transmembrane adhesion molecules with the cytoskeleton in carcinoma may be impaired as revealed by reduced levels of expression of alpha-catenin, vinculin, alpha-actinin, talin, and pp125FAK. Importantly, carcinoma cells, when exposed to stroma during invasion, do not acquire the adhesion apparatus characteristic of normal cells in contact with the extracellular matrix.
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PMID:Adhesion systems in normal breast and in invasive breast carcinoma. 788 51

CAI (NSC 609974; L651582), a new agent that has demonstrated antimetastatic activity in vitro and in vivo, was not very cytotoxic toward EMT-6 mouse mammary carcinoma cells in culture or toward FSaIIC fibrosarcoma cells in vivo. Coexposure of EMT-6 cells to CAI and antitumor alkylating agents under various environmental conditions did not markedly increase the cytotoxicity of cisplatin (CDDP), melphalan, or carmustine (BCNU). However, the combination of CAI and 4-hydroperoxycyclophosphamide (4-HC) produced much greater than additive killing of EMT-6 cells. CAI also increased the sensitivity of hypoxic EMT-6 cells to X-rays. CAI increased the cytotoxicity of cyclophosphamide toward FSaIIC tumor cells when animals were treated with single doses of both drugs. The effect of CAI on tumor cell killing by cyclophosphamide was greatest at high doses of the antitumor alkylating agent. CAI administration appeared to result in increased serum levels of prostaglandin E2 and leukotriene B4 in animals bearing the Lewis lung tumor. Administration of CAI on days 4-18 did not alter the growth of the Lewis lung carcinoma but did result in an increase in the tumor-growth delay produced by treatment with CDDP, cyclophosphamide, melphalan, BCNU, and fractionated radiation. Although CAI did not reduce the number of lung metastases present in Lewis lung carcinoma-bearing mice on day 20, it did appear to reduce the number of large (vascularized) metastases present on that day.
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PMID:CAI: effects on cytotoxic therapies in vitro and in vivo. 792 63

Anorectal lesions in patients carrying the HIV virus are uncommon (13%, in our personal life, 1 women/15 men). The following raise the possibility of AIDS: Kaposi sarcoma, non Hodgkin's lymphoma and also with the young patients, intraepithelial dysplasia, in situ carcinoma or squamous carcinoma of the anus. Other anorectal lesions encountered in proctology, should lead to suspicion of HIV infection: anal involvement in STD, florid papillomatosis, the most frequent lesion in his serious form which recur on a interminable bases, extensive and chronic herpes, lesions refractory to standard treatment, megalovirus and ulcers. Date by history indicating sexual habits, toxicomania as well as the existence of chronic diarrhea and full physical examination scoking enlarged lymph nodes are all factors to be taken into consideration in support of the diagnosis. Apart from painful emergencies justifying immediate surgery, indications for surgery should be weighed in terms of the patient's general condition, the stage of advancement of the disease and expected benefit in terms of patient comfort.
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PMID:[Update of anal-perineal and rectal lesions observed in AIDS]. 801 11

Focal adhesion kinase, pp125FAK, is a nonmyristylated cytosolic tyrosine kinase unrelated to protein-tyrosine kinase families categorized to date. The kinase activity and tyrosine phosphorylation of pp125FAK are induced by beta 1 and beta 3 integrin-mediated cell adherence or aggregation. pp125FAK is also a tyrosine phosphorylation substrate in v-src-transformed cells and is localized to focal adhesion contracts of adherent fibroblasts and carcinoma cells. In this report, we have transiently expressed in COS cells a transmembrane-anchored chimeric receptor kinase, CD2FAK, consisting of CD2 and pp125FAK. We analyzed its kinase activity and tyrosine phosphorylation and compared to those of pp125FAK. We found that CD2FAK exhibited constitutive kinase activity and a high basal tyrosine phosphorylation level when COS transfectants were suspended in serum-free media. The kinase activity of CD2FAK was similarly up-regulated upon beta 1 integrin-mediated cell adherence as the endogenous pp125FAK. Both CD2FAK and pp125FAK appeared to be active as autophosphorylating kinases as shown by mutation of the ATP binding site. We determined the major tyrosine phosphorylation site, Tyr397, identical for both the constitutively activated CD2FAK and pp125FAK in response to beta 1 integrin-mediated cell adherence by site-directed mutagenesis. Deletions of the NH2- or the COOH-terminal noncatalytic domain of FAK, including Tyr397 did not lead to abolition of the kinase activity of pp125FAK or CD2FAK. Taken together, CD2FAK exhibits properties of an activated pp125FAK and the kinase activity does not appear to require tyrosine phosphorylation in vitro or in vivo.
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PMID:A transmembrane-anchored chimeric focal adhesion kinase is constitutively activated and phosphorylated at tyrosine residues identical to pp125FAK. 805 Nov 57

There is now a considerable body of evidence that links HPV infection with anogenital squamous carcinoma, particularly for specific 'high risk' HPV types (HPV16 and 18) and invasive carcinoma of the cervix. Recent advances in the molecular study of these viruses have elucidated some potential mechanisms by which they may contribute to the development of these diseases. In this review we concentrate on the interactions of 2 of the HPV encoded proteins, E6 and E7, with cellular tumour suppressor gene products. We provide a model of how these interactions may be important in tumourigenesis and draw together current knowledge of this exciting and rapidly evolving field.
Int J STD AIDS
PMID:Human papillomaviruses, tumour suppressor genes and cervical cancer. 839 53

The cytotoxicity of the topoisomerase I inhibitors, camptothecin and topotecan, toward exponentially growing EMT-6 murine mammary carcinoma cells under various conditions of oxygenation, pH and temperature was assessed. Under normal pH (pH 7.40) conditions both camptothecin and topotecan were more cytotoxic toward normally oxygenated cells. Both agents were more cytotoxic under acidic pH (pH 6.45) and the differential in cytotoxicity due to the cellular oxygenation level disappeared. Neither camptothecin nor topotecan was enhanced in cytotoxicity by hyperthermia (42 degrees C or 43 degrees C, 60 min) during drug exposure. Both camptothecin and topotecan killed increasing numbers of FSaIIC tumor cells with increasing dose of the drugs in vivo in a log/linear manner. Local hyperthermia (43 degrees C, 30 min) increased the tumor cell killing of the drugs but decreased the toxicity of these agents to the bone marrow granulocyte/macrophage-colony-forming units. Topotecan was a more effective modulator of cisplatin than was camptothecin, as determined by FSaIIC tumor cell survival assay and by FSaIIC tumor growth delay. Although both camptothecin and topotecan were effective additions to a treatment regimen including cisplatin and daily fractionated radiation (5 x 3Gy), neither of these topoisomerase I inhibitors increased the tumor growth delay produced by the trimodality regimen of cisplatin/hyperthermia/radiation.
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PMID:Addition of a topoisomerase I inhibitor to trimodality therapy [cis-diamminedichloroplatinum(II)/heat/radiation] in a murine tumor. 839 65

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


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