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)

Normal human dermis contains mesenchymal cells that are generally referred to as fibroblasts. However the relationships between fibroblasts and endothelial cells with respect to the types of spindle-shaped cells that are present in cultures obtained from tumor bearing-skin is unclear. To explore the potential heterogeneity amongst dermal-derived cells that grow in culture with a spindle-shaped morphology, we compared the immunophenotype and growth characteristics of several types of cells. Besides dermal fibroblasts and microvascular endothelial cells derived from normal adult skin, we also studied large vessel-derived endothelial cells, and spindle-shaped cells derived from three different tumor-bearing dermal-based neoplasms. Kaposi's sarcoma (KS), dermatofibroma (DF), and dermatofibrosarcoma protuberans (DFSP). A broad panel of eight different antibodies were used to immunophenotype the multi-passaged cultured cells. Spindle-shaped cells from all three neoplasms could be distinguished from the normal skin derived fibroblasts by their constitutive expression of factor XIIIa, and the gamma-interferon induced expression of VCAM-1. All seven types of cultured cells stained positive for s-actin and proline-4-hydroxylase, and none of the cells expressed CD34. Both large and small-vessel derived endothelial cells expressed factor VIII, ELAM-1, and VCAM-1. Using two different types of growth media, significant differences were also observed amongst these cultured cell types. Spindle-shaped cells from DFSP did not grow in DMEM containing 10% fetal bovine serum (DMEM-FBS); but they proliferated in KS cell growth medium (KSGM). Spindle-shaped cells from DF grew best in KSGM, but not in DMEM-FBS. KS tumor cells grew well in KSGM, but not in DMEM-FBS. Fibroblasts proliferated in DMEM-FBS, but failed to grow in KSGM; and even when pre-treated with conditioned medium from a transformed KS cell line (i.e. SLK cells), no fibroblast proliferation could be induced in KSGM. These results indicate that KS cell line (i.e. SLK cells), no fibroblast proliferation could be induced in KSGM. These results indicate that even though dermal-derived cells can have an identical spindle-shape by light microscopy, significant heterogeneity can be defined amongst such cells from normal and tumor-bearing human skin. Having established culture conditions to propagate these different cell types and phenotypic criteria to distinguish them from one another, will provide new research opportunities to explore the function and ontogeny of the diverse mesenchymal cells that take on a spindle-shaped morphology in culture.
J Dermatol Sci 1997 Nov
PMID:Phenotype and proliferation characteristics of cultured spindle-shaped cells obtained from normal human skin and lesions of dermatofibroma, Kaposi's sarcoma, and dermatofibrosarcoma protuberans: a comparison with fibroblast and endothelial cells of the dermis. 943 8

Lectins or agglutinins are proteins with affinity for specific sugar residues. Peanut agglutinin (PNA) and the lectin from the edible mushroom (Agaricus bisporus, ABL) both bind to the disaccharide galactosyl beta-1,3-N-acetyl galactosamine alpha-. This is expressed in keratinocytes as an O-linked chain on CD44, a polymorphic membrane glycoprotein. Many lectins are mitogens and PNA is a mitogen for colonic epithelial cells. However, ABL reversibly inhibits proliferation of colonic cancer cell lines without cytotoxicity and thus has therapeutic potential in situations such as psoriasis where proliferation is increased. We have therefore investigated the effect of ABL on the growth of normal human cultured keratinocytes and a human papilloma virus (HPV)-transformed cell line. In a 5-day dose-response study, keratinocyte growth was greatly reduced by 1.0 microg/mL ABL and completely inhibited by 3.0 microg/mL ABL (ANOVA, P < 0.0001). Exposure to 1.0 microg/mL ABL for only 8 h gave the same growth inhibition as did continued exposure for 3 days. No cytotoxic or morphological changes were observed. An HPV-immortalized cell line was relatively resistant to ABL: in a 5-day dose-response study, exposure to 30 microg/mL was required to inhibit cell growth completely. Topical application of ABL 0.01% or 0.1% to normal human skin caused no change in skin erythema, blood flow or thickness compared with vehicle or baseline (n = 6). ABL 0. 1% in white soft paraffin was compared with vehicle in 11 psoriatic patients, using comparative contralateral plaques. Twice daily application for 2 weeks showed no significant difference from vehicle-treated sites, although the skin thickness of plaques fell from 5.3 +/- 0.4 (n = 11, mean +/- SEM) to 4.1 +/- 0.3 mm. In view of the in vitro results further studies are warranted, particularly if means can be found to improve the epidermal penetration of the relatively large ABL molecule (60 kDa).
Br J Dermatol 1999 Jan
PMID:The antiproliferative effect of lectin from the edible mushroom (Agaricus bisporus) on human keratinocytes: preliminary studies on its use in psoriasis. 1021 68

Previous findings indicate that the protein c-KIT and its ligand, stem cell factor (SCF) play a crucial role in the development of melanocytes from their precursors in the embryonic neural crest cells. Using a monoclonal anti-c-KIT antibody, ACK2, which is an antagonistic blocker of c-KIT function, we and colleagues demonstrated that mouse melanocytes disappeared with the injection of ACK2 during certain periods of embryonic and postnatal life. The precise mechanisms of this disappearance, however, remain unclear. Because melanocytes disappeared without any inflammation in these in vivo studies, we suspect that apoptosis was a main cause of their disappearance. In this study, to clarify the underlying mechanism, we studied whether ACK2 induces apoptosis in c-KIT-positive melanoblasts, which appear in mouse neural crest cells cultured with SCF from 9.5 d old mouse embryos. With an in situ apoptosis detection kit, a significant increase in apoptosis was detected after the removal of SCF, which further increased with the addition of ACK2 during SCF-dependent periods. The occurrence of apoptosis in the cultured cells was also demonstrated by a DNA analysis and electron microscopy. Immunohistochemical double staining confirmed that the apoptotic cells were c-KIT positive, and the electron microscopy showed that these apoptotic cells were melanocyte precursors. It was therefore demonstrated that apoptosis was induced in the SCF-dependent c-KIT-positive melanocytes in vitro when the SCF/c-KIT interaction was obstructed. These findings elucidate the mechanism of the regulation of melanocyte development, and the survival and proliferation of these precursor cells, by SCF/c-KIT interaction.
J Invest Dermatol 1999 May
PMID:Removal of stem cell factor or addition of monoclonal anti-c-KIT antibody induces apoptosis in murine melanocyte precursors. 1023 74

Cytosolic sulfotransferases (ST) catalyze the sulfation of various phenolic agents, catecholamines, thyroid hormones, steroids, drugs, and procarcinogens, usually resulting in the inactivation and subsequent excretion of the compound. My laboratory's efforts have focused on the cloning of the human phenol-sulfating (PST) members of this gene superfamily, implicated in the bioactivation of the hair growth stimulant, minoxidil. At least two major forms of human PST enzymes have been characterized biochemically, the phenol-preferring PST (P-PST), and the catecholamine-preferring PST (M-PST). Various cDNAs have been cloned representing alleles of 3 gene loci termed as STP1, STP2, and STM, which were all mapped precisely to a small region on human chromosome 16p and to the homologous region of mouse chromosome 7. Human cosmid genomic clones have been sequenced to determine the genomic organization for each of the 3 highly-related genes. All contain 7 coding exons, with conserved intron-exon boundaries, and presumptive alternative tissue-specific promoters. At least one of the 3 PST-encoding genes is responsible for forming minoxidil sulfate in the lower outer root sheath of anagen hair follicles. The steroid sulfating genes, STD and STE, have been cloned by other laboratories. The isozyme products of these genes sulfate DHEA and estrogens, respectively. I hypothesize that either STE or STD is involved in the formation of cholesterol sulfate (CS) in epidermal keratinocytes. CS has been demonstrated by other groups to be an activator of keratinocyte Protein Kinase Ceta, which subsequently results in the activation of epidermal transglutaminase and formation of the cornified envelop. STE or STD might also be involved in bioinactivation of estrogens and androgens within skin. Our recent unpublished results have focused on elucidating the patterns of ST gene expression in cultured keratinocytes and fibroblasts derived from human skin using RT-PCR, to understand which of the 5 different ST genes in involved in the regulation of keratinocyte differentiation and minoxidil-induced hair growth.
Exp Dermatol 1999 Aug
PMID:Molecular biology of the human cytosolic sulfotransferase gene superfamily implicated in the bioactivation of minoxidil and cholesterol in skin. 1043 54

beta1-integrins play crucial roles in a variety of cell processes such as adhesion, migration, proliferation, and differentiation of lymphocytes. For understanding the molecular mechanisms of these various biological effects, it may be particularly important to analyze cell signaling through the beta1-integrins. Our previous study had shown that PLC-gamma, pp125FAK (focal adhesion kinase), pp105, paxillin, p59fyn, p56lck and ERK1/2 are phosphorylated in their tyrosine residues upon engagement of beta1-integrins. We identified pp105 as Cas (Crk-associated substrate)-related protein and successfully cloned its cDNA. pp105 is a Cas homologue predominantly expressed in the cells of lymphoid lineage, which led us to designate it as Cas-L. Like p130Cas, Cas-L contains a single SH3 domain and multiple SH2 binding sites (YXXP motif), which is suggested to bind SH2 domains of Crk, Nck, and SHPTP2. Subsequent studies revealed that pp125FAK binds Cas-L on its SH3 domain and phosphorylates its tyrosine residues upon beta1-integrin stimulation. Since Cas-L is preferentially expressed in lymphocytes, it is conceivable that Cas-L plays an important role in lymphocyte-specific signals. We have shown that Cas-L is involved in the T-cell receptor (TCR)/CD3 signaling pathway as well as the beta1-integrin signaling pathway. Cas-L is transiently phosphorylated following CD3 cross-linking, and tyrosine-phosphorylated Cas-L binds to Crk and C3G. Furthermore, a Cas-L mutant (Cas-LDeltaSH3), which lacks the binding site for FAK, is still tyrosine-phosphorylated upon CD3 cross-linking, but not upon beta1-integrin cross-linking, suggesting that FAK is not involved in CD3-dependent Cas-L phosphorylation. Finally, we have identified a crucial role of Cas-L in beta1-integrin-mediated T-cell co-stimulation. beta1-integrins have known to provide a co-stimulus for TCR/CD3-driven interleukin-2 production and proliferation of peripheral T-cells. We have found that this co-stimulatory pathway is impaired in the Jurkat T-cell line, and that the expression level of Cas-L is reduced in Jurkat cells compared with peripheral T-cells. The transfection of Cas-L cDNA into Jurkat cells restored the beta1-integrin-mediated co-stimulation, while the transfection of Cas-LDeltaSH3 mutant failed to do so, showing a contrast to the case with CD3-mediated signaling. These results indicate that Cas-L plays a key role through the association and phosphorylation by FAK in the beta1-integrin-mediated T-cell co-stimulation. Taken together, Cas-L might be the bi-modal docking protein that assembles the signals through beta1-integrins and TCR/CD3, and participates in a variety of T-cell functions.
J Dermatol Sci 2000 Jun
PMID:Beta 1-integrin-mediated cell signaling in T lymphocytes. 1080 24

During the 1990s, no studies of various clinical presentations of syphilis have been published in the indexed literature. However, a change in the clinical profile of secondary syphilis was expected during the last decade with the rapid spread of the HIV epidemic. The objective was to study the mucocutaneous manifestations of secondary syphilis in patients attending the STD clinic at the Postgraduate Institute of Medical Education & Research Chandigarh, India, during the last decade and to compare them with other similar studies published during the 1980s. All patients who were diagnosed with secondary syphilis in our STD clinic from 1990 to 1999 were examined and investigated. Serological response was measured at 3, 6, 9, 12, and 24 months post-treatment or until serological negativity was reached. Fifty-three patients (males = 34, female = 19) during this period were found to have secondary syphilis. The most common symptoms were as follows-skin rash 38 (71.7%), lymphadenopathy 26 (49%), persistent chancre 4 (7.5%), nodular syphilides 2 (3.8%), lues maligna 2 (3.8%), patches in the oral mucosa 6 (11.3%), condylomata lata 14 (26.4%), split papules 2 (3.8%). Five patients had a thin and conspicuous genital scar of the healed primary chancre. Three patients were HIV seropositive (1 patient each with lues maligna, lichenoid, and nodular syphilides). With the spread of the HIV epidemic, atypical muco-cutaneous manifestations of secondary syphilis may be seen more frequently than before and may pose problems in diagnosis. In the present study, six patients had atypical manifestations, and three of them were HIV seropositive.
J Dermatol 2001 Mar
PMID:Mucocutaneous manifestations of secondary syphilis in north Indian patients: a changing scenario? 1134 64

Development of cytokine resistance is an important feature of melanoma cells during tumor progression. To study the mechanisms of interleukin-6 resistance, we examined an interleukin-6 sensitive (WM35) and an interleukin-6 unresponsive cell line (WM9). Interleukin-6 treatment resulted in rapid inhibition of cyclin-dependent kinase 2/cyclin E activity and accumulation of the hypophosphorylated retinoblastoma protein in WM35 but not in WM9 cells. In contrast to previous reports, no differences in the expression of the cyclin-dependent kinase 2 inhibitor p21Cip1/WAF1 upon interleukin-6 treatment were found in both cell lines. Interleukin-6-induced inhibition of cyclin-dependent kinase 2 was also not due to changes in protein expression of cyclin-dependent kinase 2, cyclin E, p27Kip1 and cdc25A, a phosphatase positively regulating cyclin-dependent kinase 2 activity. As it is established that interleukin-6 resistance of WM9 cells is not caused by differential interleukin-6 receptor expression, we studied whether this is due to defective interleukin-6 signaling in which activation of signal transducer and activator of transcription 3 is a critical step. WM9 cells showed reduced tyrosine phosphorylation, DNA binding, and delayed nuclear translocation of signal transducer and activator of transcription 3 as compared with WM35 cells. The kinase upstream of signal transducer and activator of transcription 3, Janus kinase 1, was constitutively tyrosine-phosphorylated in WM9 cells and did not respond to interleukin-6 with increased phosphorylation. As compared with WM35 cells, interleukin-6 treatment of WM9 cells was not paralleled by reduced activity of the mitogen-activated protein kinase kinase-1, which suppresses activation of signal transducer and activator of transcription 3. Our data suggest that resistance of advanced melanoma cells to interleukin-6 is associated with reduced inhibition of cyclin-dependent kinase 2, which appears to be a consequence of a complex alteration in interleukin-6 signal transduction.
J Invest Dermatol 2001 Jul
PMID:Interleukin-6-resistant melanoma cells exhibit reduced activation of STAT3 and lack of inhibition of cyclin E-associated kinase activity. 1144 60

Cell spreading, proliferation, and survival are modulated by focal adhesions linking extracellular matrix proteins, integrins, and the cytoskeleton. Zyxin is a focal-adhesion-associated phosphoprotein with one domain involved in the control of actin assembly and three protein-protein adapter domains implicated in the regulation of cell growth and differentiation. We characterized zyxin expression in normal human melanocytes and six melanoma cell lines in relation to cell spreading, growth, and differentiation using Western immunoblotting techniques, image analysis, flow cytometry, and confocal microscopy. We found that zyxin, focal adhesion kinase, and paxillin were significantly upregulated in melanoma cells compared to melanocytes. Zyxin expression directly related to cell spreading and proliferation and inversely related to differentiation, whereas focal adhesion kinase correlated only to cell spreading and paxillin did not significantly correlate with any of the parameters. Treatment of melanoma cells with 12-O-tetradecanoylphorbol-13-acetate downregulated zyxin expression, inhibited cell spreading and proliferation, and promoted differentiation. In contrast, 12-O-tetradecanoylphorbol-13-acetate, a mitogen for melanocytes, induced upregulation of zyxin expression in melanocytes. These findings are consistent with a role of zyxin in modulation of cell spreading, proliferation, and differentiation. Therapies directed at the downregulation of this focal adhesion phosphoprotein in melanoma cells implicate a new approach for controlling melanoma cell growth.
J Invest Dermatol 2002 Feb
PMID:Role of zyxin in differential cell spreading and proliferation of melanoma cells and melanocytes. 1184 40

We previously proposed that the keratinocyte hyperproliferative state in psoriatic skin results from a combination of T cell cytokine interaction with basal keratinocytes that exist in a primed state. We now provide evidence that basal keratinocytes from psoriatic uninvolved skin are in a preactivated state with regard to their interaction with fibronectin. Freshly isolated basal keratinocytes (K(1)/K(10)(-)) from non-lesional psoriatic skin demonstrated a significantly higher percentage of spreading cells 1 h after plating on fibronectin-coated plates than keratinocytes isolated from normal skin (p =0.0002). No differences were observed on collagen-laminin-coated plates, however. The keratinocyte spreading on fibronectin-coated plates involved alpha 5 beta 1 and alpha V beta 1 integrins. To address the potential signaling cascades that may respond to integrin changes in psoriatic keratinocytes, focal adhesion kinase changes were assessed. The percentage of keratinocytes from psoriatic uninvolved skin that exhibit positive focal adhesion kinase staining was significantly greater than the percentage from healthy volunteers after 1 h incubation on fibronectin (p =0.006). Additionally, focal adhesion kinase isolated from uninvolved psoriatic keratinocytes had a greater degree of tyrosine phosphorylation. Thus, the proliferative effect of fibronectin in combination with T cell lymphokines on psoriatic uninvolved basal keratinocyte progenitors may be due to abnormal in vivo integrin-driven focal adhesion kinase activity and downstream signaling.
J Invest Dermatol 2001 Dec
PMID:Basal keratinocytes from uninvolved psoriatic skin exhibit accelerated spreading and focal adhesion kinase responsiveness to fibronectin. 1188 20

Autocrine growth of human epidermal keratinocytes can be maintained in subconfluent cell cultures in the absence of exogenous growth factors. We used this culture model to investigate the interactions between the mitogen-activated protein kinase (MAPK) pathway and Ca(2+)/calmodulin-dependent protein kinases (CaM-kinases) in autocrine keratinocyte proliferation. We have previously demonstrated that MAPK and protein kinase C (PKC) are both involved in keratinocyte proliferation in a complex set of interactions. Treatment of keratinocytes with PD98059, a potent inhibitor of MAPK kinase, inhibited the MAPK pathway, c-myc activation and autocrine keratinocyte proliferation. Application of the CaM-kinase inhibitor KN-62 also led to a strong inhibition of MAPK/c-myc activation and autocrine keratinocyte proliferation. Other inhibitors, such as wortmannin (selective and potent inhibitor of phosphatidylinositol 3-kinase) and AG 490 (JAK2 inhibitor) had weak effects on autocrine keratinocyte proliferation, MAPK and c-myc activation. Our results clearly demonstrate a crosstalk between CaM-kinase/MAPK pathways in transducing keratinocyte proliferation stimuli.
Arch Dermatol Res 2002 Jul
PMID:Ca(2+)/calmodulin-dependent protein kinase (CaM-kinase) inhibitor KN-62 suppresses the activity of mitogen-activated protein kinase (MAPK), c-myc activation and human keratinocyte proliferation. 1211 51


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