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Journal ArticleDOI

Melanoma chondroitin sulfate proteoglycan enhances FAK and ERK activation by distinct mechanisms

21 Jun 2004-Journal of Cell Biology (Rockefeller University Press)-Vol. 165, Iss: 6, pp 881-891

TL;DR: Results indicate that MCSP may facilitate primary melanoma progression by enhancing the activation of key signaling pathways important for tumor invasion and growth.

AbstractMelanoma chondroitin sulfate proteoglycan (MCSP) is an early cell surface melanoma progression marker implicated in stimulating tumor cell proliferation, migration, and invasion. Focal adhesion kinase (FAK) plays a pivotal role in integrating growth factor and adhesion-related signaling pathways, facilitating cell spreading and migration. Extracellular signal–regulated kinase (ERK) 1 and 2, implicated in tumor growth and survival, has also been linked to clinical melanoma progression. We have cloned the MCSP core protein and expressed it in the MCSP-negative melanoma cell line WM1552C. Expression of MCSP enhances integrin-mediated cell spreading, FAK phosphorylation, and activation of ERK1/2. MCSP transfectants exhibit extensive MCSP-rich microspikes on adherent cells, where it also colocalizes with α4 integrin. Enhanced activation of FAK and ERK1/2 by MCSP appears to involve independent mechanisms because inhibition of FAK activation had no effect on ERK1/2 phosphorylation. These results indicate that MCSP may facilitate primary melanoma progression by enhancing the activation of key signaling pathways important for tumor invasion and growth.

Topics: CSPG4 (59%), Chondroitin Sulfate Proteoglycan 4 (53%), Focal adhesion (53%), Signal transduction (52%), MAPK/ERK pathway (52%)

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Citations
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Journal ArticleDOI
TL;DR: Work with model systems in vivo and in vitro reveals roles in growth, adhesion, migration, and metabolism in transmembrane proteoglycans, and a wide range of phenotypes for the core proteins has been obtained in mouse knockout experiments.
Abstract: Virtually all metazoan cells contain at least one and usually several types of transmembrane proteoglycans. These are varied in protein structure and type of polysaccharide, but the total number of vertebrate genes encoding transmembrane proteoglycan core proteins is less than 10. Some core proteins, including those of the syndecans, always possess covalently coupled glycosaminoglycans; others do not. Syndecan has a long evolutionary history, as it is present in invertebrates, but many other transmembrane proteoglycans are vertebrate inventions. The variety of proteins and their glycosaminoglycan chains is matched by diverse functions. However, all assume roles as coreceptors, often working alongside high-affinity growth factor receptors or adhesion receptors such as integrins. Other common themes are an ability to signal through their cytoplasmic domains, often to the actin cytoskeleton, and linkage to PDZ protein networks. Many transmembrane proteoglycans associate on the cell surface with metzincin proteases and can be shed by them. Work with model systems in vivo and in vitro reveals roles in growth, adhesion, migration, and metabolism. Furthermore, a wide range of phenotypes for the core proteins has been obtained in mouse knockout experiments. Here some of the latest developments in the field are examined in hopes of stimulating further interest in this fascinating group of molecules.

319 citations


Cites background from "Melanoma chondroitin sulfate proteo..."

  • ...NG2 is also present in proliferative cells and is upregulated in many tumor types; the human form takes its name from the melanoma source from which it was characterized (Yang et al. 2004)....

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  • ...Expression of the MCSP/NG2 proteoglycan leads to Erk activation and localization of the proteoglycan, this time with α4β1 integrin on apical filopodia (Yang et al. 2004)....

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  • ...Syntenin, a PDZ domain protein, interacts with the Cterminal regions of syndecans and MCSP/NG2 and has been shown to promote melanoma cell motility though interactions with c-Src and a complex with FAK, signaling to p38 and NF-κB, and MMP2 production (Yang et al. 2004)....

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Journal ArticleDOI
TL;DR: Encouraging results in animal studies and clinical trials show the clinical relevance of glycosaminoglycan-based drugs and the use of glyCosaminoglycans as therapeutic targets.
Abstract: Glycosaminoglycans are unbranched polysaccharides composed of repeating units of alternating uronic acids and amino sugars. Most glycosaminoglycans are covalently attached to core proteins to form proteoglycans. Posttranslational modifications result in specific motifs that bind to a large variety of ligands, thus regulating growth factor signaling, cellular behavior, inflammation, angiogenesis, and the proteolytic environment. Dysregulated expression of glycosaminoglycans is present in cancer and reported to correlate with clinical prognosis in several malignant neoplasms. Recent knowledge on the biological roles of these molecules in cancer biology, tumor angiogenesis, and metastasis has promoted the development of drugs targeting them. Pharmaceutical approaches include the use of chemically modified heparins and glycosaminoglycans with defined structures, combination of inhibitors of glycosaminoglycan biosynthesis and polyamine depletion, and biologically active glycosaminoglycan-binding peptides. In addition, glycosaminoglycans are used as tumor-specific delivery and targeting vehicles for toxins and chemotherapeutics. Encouraging results in animal studies and clinical trials show the clinical relevance of glycosaminoglycan-based drugs and the use of glycosaminoglycans as therapeutic targets.

239 citations


Additional excerpts

  • ...extracellular signal–regulated kinase activation (8), and the...

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Journal ArticleDOI
01 Apr 2012-Brain
TL;DR: The data show the physiological relevance of the peptidome approach and provide a critical advance for designing a rational glioblastoma immunotherapy, and the peptides identified in this study are currently being tested as a multipeptide vaccine in patients with gliOBlastoma.
Abstract: Peptides presented at the cell surface reflect the protein content of the cell; those on HLA class I molecules comprise the critical peptidome elements interacting with CD8 T lymphocytes. We hypothesize that peptidomes from ex vivo tumour samples encompass immunogenic tumour antigens. Here, we uncover >6000 HLA-bound peptides from HLA-A*02(+) glioblastoma, of which over 3000 were restricted by HLA-A*02. We prioritized in-depth investigation of 10 glioblastoma-associated antigens based on high expression in tumours, very low or absent expression in healthy tissues, implication in gliomagenesis and immunogenicity. Patients with glioblastoma showed no T cell tolerance to these peptides. Moreover, we demonstrated specific lysis of tumour cells by patients' CD8(+) T cells in vitro. In vivo, glioblastoma-specific CD8(+) T cells were present at the tumour site. Overall, our data show the physiological relevance of the peptidome approach and provide a critical advance for designing a rational glioblastoma immunotherapy. The peptides identified in our study are currently being tested as a multipeptide vaccine (IMA950) in patients with glioblastoma.

147 citations


Cites background or methods from "Melanoma chondroitin sulfate proteo..."

  • ...As foreseen with the design of the selection strategy, the 10 GBMassociated antigens are involved in tumourigenic mechanisms (Supplementary Table 2) such as tumour cell motility, proliferation, invasion or angiogenesis (Sehgal et al., 1998; Kim et al., 2000; Chekenya et al., 2002; Yang et al., 2004; Phillips et al., 2006; Mita et al., 2007; Hu et al., 2008)....

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  • ...…GBMassociated antigens are involved in tumourigenic mechanisms (Supplementary Table 2) such as tumour cell motility, proliferation, invasion or angiogenesis (Sehgal et al., 1998; Kim et al., 2000; Chekenya et al., 2002; Yang et al., 2004; Phillips et al., 2006; Mita et al., 2007; Hu et al., 2008)....

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Journal ArticleDOI
04 Sep 2008-Oncogene
TL;DR: NG2/MPG knockdown with shRNAs incorporated into lentiviral vectors attenuated β1 integrin signaling revealing potent antitumor effects and further sensitized neoplastic cells to cytotoxic treatment in vitro and in vivo may represent an effective therapeutic target in several cancer subtypes.
Abstract: Chemoresistance represents a major problem in the treatment of many malignancies. Overcoming this obstacle will require improved understanding of the mechanisms responsible for this phenomenon. The progenitor cell marker NG2/melanoma proteoglycan (MPG) is aberrantly expressed by various tumors, but its role in cell death signaling and its potential as a therapeutic target are largely unexplored. We have assessed cytotoxic drug-induced cell death in glioblastoma spheroids from 15 patients, as well as in five cancer cell lines that differ with respect to NG2/MPG expression. The tumors were treated with doxorubicin, etoposide, carboplatin, temodal, cisplatin and tumor necrosis factor (TNF)alpha. High NG2/MPG expression correlated with multidrug resistance mediated by increased activation of alpha3beta1 integrin/PI3K signaling and their downstream targets, promoting cell survival. NG2/MPG knockdown with shRNAs incorporated into lentiviral vectors attenuated beta1 integrin signaling revealing potent antitumor effects and further sensitized neoplastic cells to cytotoxic treatment in vitro and in vivo. Thus, as a novel regulator of the antiapoptotic response, NG2/MPG may represent an effective therapeutic target in several cancer subtypes.

136 citations


Cites background from "Melanoma chondroitin sulfate proteo..."

  • ...Since NG2/MPG has been shown to interact with b1 integrins (Burg et al., 1998; Eisenmann et al., 1999; Fukushi et al., 2004; Yang et al., 2004), we investigated whether b1 integrin signaling could be involved in NG2/MPG-mediated resistance to cell death....

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Journal ArticleDOI
TL;DR: The antitumor activity of CSPG4-specific mAb was mediated by multiple mechanisms, including the inhibition of signaling pathways crucial for TNBC cell survival, proliferation, and metastasis, and was identified as a new target for T NBC.
Abstract: Background The cell surface proteoglycan, chondroitin sulfate proteoglycan 4 (CSPG4), is a potential target for monoclonal antibody (mAb)–based immunotherapy for many types of cancer. The lack of effective therapy for triple-negative breast cancer (TNBC) prompted us to examine whether CSPG4 is expressed in TNBC and can be targeted with CSPG4-specific mAb.

127 citations


References
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Journal ArticleDOI
TL;DR: Focal adhesions are sites of tight adhesion to the underlying extracellular matrix developed by cells in culture and are regions of signal transduction that relate to growth control.
Abstract: Focal adhesions are sites of tight adhesion to the underlying extracellular matrix developed by cells in culture. They provided a structural link between the actin cytoskeleton and the extracellular matrix and are regions of signal transduction that relate to growth control. The assembly of focal adhesions is regulated by the GTP-binding protein Rho. Rho stimulates contractility which, in cells that are tightly adherent to the substrate, generates isometric tension. In turn, this leads to the bundling of actin filaments and the aggregation of integrins (extracellular matrix receptors) in the plane of the membrane. The aggregation of integrins activates the focal adhesion kinase and leads to the assembly of a multicomponent signaling complex.

1,905 citations


"Melanoma chondroitin sulfate proteo..." refers background in this paper

  • ...Melanoma cells overexpressing FRNK still form microspikes, but lack the ability to extend their leading edges to the same extent as mock-infected cells, consistent with a model in which FRNK interferes with the inhibition of the RhoA/myosin pathway in these cells (Wakatsuki et al., 2003)....

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  • ...Although small GTPases such as Cdc42 are associated with actin-mediated formation of leading edges in spreading/migrating cells, FAK can facilitate cell spreading in part by inhibiting the activation of RhoA (Burridge and Chrzanowska-Wodnicka, 1996; Wakatsuki et al., 2003)....

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Journal ArticleDOI
TL;DR: As cancer cells undergo metastasis — invasion and migration of a new tissue — they penetrate and attach to the target tissue's basal matrix, which allows the cancer cell to pull itself forward into the tissue.
Abstract: As cancer cells undergo metastasis--invasion and migration of a new tissue--they penetrate and attach to the target tissue's basal matrix. This allows the cancer cell to pull itself forward into the tissue. The attachment is mediated by cell-surface receptors known as integrins, which bind to components of the extracellular matrix. Integrins are crucial for cell invasion and migration, not only for physically tethering cells to the matrix, but also for sending and receiving molecular signals that regulate these processes.

1,656 citations


"Melanoma chondroitin sulfate proteo..." refers background in this paper

  • ...MCSP is also associated with the transmembrane matrix metalloproteinase MT3-MMP on VGP melanoma cells, and in vitro facilitates invasion into type I collagen gels as well as degradation of denatured type I collagen (Iida et al., 2001)....

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  • ...Altered expression of a number of integrins has been linked to the progression of malignant melanoma, and increased expression of 4 1 integrin is associated with transformation from RGP to VGP (Johnson, 1999; Hood and Cheresh, 2002)....

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  • ...Altered expression of a number of integrins has been linked to the progression of malignant melanoma, and increased expression of 4 1 integrin is associated with transformation from RGP to VGP (Johnson, 1999; Hood and Cheresh, 2002)....

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  • ...Overexpression of FRNK in either the VGP WM1341D cells (Figs....

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  • ...Phosphorylated ERK (pERK) 1/2 was easily detected in the VGP WM1341D cells (Fig....

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Journal ArticleDOI
12 Aug 1994-Science
TL;DR: It is found that constitutive activation of MAPKK is sufficient to promote cell transformation and is associated with highly tumorigenic in nude mice.
Abstract: Mitogen-activated protein (MAP) kinase kinase (MAPKK) activates MAP kinase in a signal transduction pathway that mediates cellular responses to growth and differentiation factors. Oncogenes such as ras, src, raf, and mos have been proposed to transform cells by prolonging the activated state of MAPKK and of components downstream in the signaling pathway. To test this hypothesis, constitutively active MAPKK mutants were designed that had basal activities up to 400 times greater than that of the unphosphorylated wild-type kinase. Expression of these mutants in mammalian cells activated AP-1-regulated transcription. The cells formed transformed foci, grew efficiently in soft agar, and were highly tumorigenic in nude mice. These findings indicate that constitutive activation of MAPKK is sufficient to promote cell transformation.

1,285 citations


"Melanoma chondroitin sulfate proteo..." refers background in this paper

  • ...Constitutive activation of ERK 1 and 2 is associated with more advanced melanoma tumors, where it promotes anchorageindependent growth and survival (Mansour et al., 1994; Conner et al., 2003; Satyamoorthy et al., 2003)....

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Journal ArticleDOI
TL;DR: FAK re-expression in the FAK- cells confirms the role of this PTK in the regulation of cell morphology and in promoting cell migration events and reinforces the potential role for FAK in promoting an invasive phenotype in human tumors.
Abstract: Integrin receptor binding to extracellular matrix proteins generates intracellular signals via enhanced tyrosine phosphorylation events that are important for cell growth, survival, and migration. This review will focus on the functions of the focal adhesion kinase (FAK) protein-tyrosine kinase (PTK) and its role in linking integrin receptors to intracellular signaling pathways. FAK associates with several diAerent signaling proteins such as Src-family PTKs, p130 Cas , Shc, Grb2, PI 3-kinase, and paxillin. This enables FAK to function within a network of integrin-stimulated signaling pathways leading to the activation of targets such as the ERK and JNK/mitogen-activated protein kinase pathways. Focus will be placed on the structural domains and sites of FAK tyrosine phosphorylation important for FAKmediated signaling events and how these sites are conserved in the FAK-related PTK, Pyk2. We will review what is known about FAK activation by integrin receptor-mediated events and also non-integrin stimuli. In addition, we discuss the emergence of a consensus FAK substrate phosphorylation sequence. Emphasis will also be placed on the role of FAK in generating cell survival signals and the cleavage of FAK during caspase-mediated apoptosis. An in-depth discussion will be presented of integrin-stimulated signaling events occurring in the FAK knockout fibroblasts (FAK ˇ ) and how these cells exhibit deficits

1,235 citations


"Melanoma chondroitin sulfate proteo..." refers background or result in this paper

  • ...MCSP expression enhances phosphorylation of FAK and ERK1/2 Because FAK is a key member of integrin-mediated signaling pathways and initial cell spreading is regulated partly through FAK activity in many cells (Guan, 1997; Schlaepfer et al., 1999), we tested whether MCSP could induce FAK activation....

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  • ...Although links between FAK activation and stimulation of the RAS/MAPK pathway have been reported (Schlaepfer et al., 1999), this finding is consistent with the many reports showing that integrin-mediated activation of MAPK can also occur via FAK-independent mechanisms (Lin et al....

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  • ...Although links between FAK activation and stimulation of the RAS/MAPK pathway have been reported (Schlaepfer et al., 1999), this finding is consistent with the many reports showing that integrin-mediated activation of MAPK can also occur via FAK-independent mechanisms (Lin et al., 1997; Barberis et…...

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  • ...The ERK/MAPK pathway has been implicated in cell spreading and is one of the downstream effectors of activated FAK (Guan, 1997; Schlaepfer et al., 1999)....

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  • ...Because FAK is a key member of integrin-mediated signaling pathways and initial cell spreading is regulated partly through FAK activity in many cells (Guan, 1997; Schlaepfer et al., 1999), we tested whether MCSP could induce FAK activation....

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01 Jan 2000
Abstract: Here we show that cells lacking focal adhesion kinase (FAK) are refractory to motility signals from platelet-derived and epidermal growth factors (PDGF and EGF respectively), and that stable re-expression of FAK rescues these defects. FAK associates with activated PDGF- and EGF-receptor (PDGFR and EGFR) signalling complexes, and expression of the band-4.1-like domain at the FAK amino terminus is sufficient to mediate an interaction with activated EGFR. However, efficient EGF-stimulated cell migration also requires FAK to be targeted, by its carboxy-terminal domain, to sites of integrin-receptor clustering. Although the kinase activity of FAK is not needed to promote PDGF- or EGF-stimulated cell motility, kinase-inactive FAK is transphosphorylated at the indispensable Src-kinase-binding site, FAK Y397, after EGF stimulation of cells. Our results establish that FAK is an important receptor-proximal link between growth-factor-receptor and integrin signalling pathways.

1,115 citations


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