Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Over the last few years, it has become clear that cell adhesion receptors function in signal transduction processes leading to the regulation of cell growth and differentiation. Signal transduction by both integrins and CAMs has been shown to involve activation of tyrosine kinases, while CAM signaling in neural cells involves G proteins as well. In the case of integrins, some of the downstream signaling events intersect with the Ras pathway, particularly the activation of MAP kinases. In fibroblasts, integrin mediated anchorage to the substratum regulates cell cycle traverse, while in epithelial cells, loss of anchorage can trigger programmed cell death. In many cell types, but particularly monocytic cells, integrin ligation has a profound impact on gene expression. Preliminary evidence also implicates CAMs and selectins in gene regulation. A consistent theme in signal transduction mediated by adhesion receptors concerns the role of the cytoskeleton. Integrin mediated signaling processes are interrupted by cytoskeletal disassembly. Identification of the APC and neurofibromatosis type 2 tumor suppressors suggest that cytoskeletal complexes also play a key role in signaling by cadherins and CD44, respectively. Thus, signaling by cell adhesion receptors may involve aspects that impinge on previously known signaling pathways including the RTK/Ras pathway and serpentine receptor/G protein pathways. However, novel aspects of signal transduction involving cytoskeletal assemblies may also be critical.
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PMID:Signal transduction by cell adhesion receptors. 754 26

CD44 has been implicated in tumor progression and metastasis, but the mechanism(s) involved is as yet poorly understood. Recent studies have shown that CD44 isoforms containing the alternatively spliced exon v3 carry heparan sulfate side chains and are able to bind heparin-binding growth factors. In the present study, we have explored the possibility of a physical and functional interaction between CD44 and hepatocyte growth factor/scatter factor (HGF/SF), the ligand of the receptor tyrosine kinase c-Met. The HGF/SF-c-Met pathway mediates cell growth and motility and has been implicated in tumor invasion and metastasis. We demonstrate that a CD44v3 splice variant efficiently binds HGF/SF via its heparan sulfate side chain. To address the functional relevance of this interaction, Namalwa Burkitt's lymphoma cells were stably co-transfected with c-Met and either CD44v3 or the isoform CD44s, which lacks heparan sulfate. We show that, as compared with CD44s, CD44v3 promotes: (i) HGF/SF-induced phosphorylation of c-Met, (ii) phosphorylation of several downstream proteins, and (iii) activation of the MAP kinases ERK1 and -2. By heparitinase treatment and the use of a mutant HGF/SF with greatly decreased affinity for heparan sulfate, we show that the enhancement of c-Met signal transduction induced by CD44v3 was critically dependent on heparan sulfate moieties. Our results identify heparan sulfate-modified CD44 (CD44-HS) as a functional co-receptor for HGF/SF which promotes signaling through the receptor tyrosine kinase c-Met, presumably by concentrating and presenting HGF/SF. As both CD44-HS and c-Met are overexpressed on several types of tumors, we propose that the observed functional collaboration might be instrumental in promoting tumor growth and metastasis.
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PMID:Heparan sulfate-modified CD44 promotes hepatocyte growth factor/scatter factor-induced signal transduction through the receptor tyrosine kinase c-Met. 1003 43

Differential gene expression through alternative pre-mRNA splicing is crucial to various physiological and pathological conditions. Upon activation of B and T lymphocytes during an immune response, variant isoforms of the cell surface molecule CD44 are generated by alternative pre-mRNA splicing. We show here that in primary mouse T cells as well as in the murine LB-17 T-cell line upregulation of variant CD44 mRNA species upon T-cell activation requires activation of the MEK-ERK pathway. By employing mutant signaling molecules and a novel luciferase-based splice reporter system we demonstrate that the Ras-Raf-MEK-ERK signaling cascade, but not the p38 MAP-kinase pathway, activates a mechanism that retains variant CD44 exon v5 sequence in mature mRNA. The findings demonstrate that a highly conserved pleiotropic signaling pathway links extracellular cues to splice regulation, providing an avenue for tissue-specific, developmental or pathology-associated splicing decisions.
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PMID:Regulation of alternative pre-mRNA splicing by the ERK MAP-kinase pathway. 1148 22

CD44v6 is transiently expressed during T cell activation, and constitutively CD44v4-v7 expressing transgenic T cells show accelerated responses towards nominal antigens. The underlying mechanism is unknown. The mouse thymoma EL4 was transfected with CD44 standard isoform (CD44s) or CD44v6 cDNA (EL4-s, EL4-v6). Only EL4-v6 cells proliferated at an over 10-fold higher rate than untransfected cells, displayed up-regulated expression of CD69, CD25, and IL-2, and were protected from apoptosis by CD44v6 cross-linking. In the absence of any stimulus, ERK1/2 was partly phosphorylated, and phosphorylation was significantly increased by CD44v6 cross-linking. The same accounted for JNK, c-jun, and IkappaBalpha. Moreover, NF-kappaB was partly translocated into the nucleus. Instead, CD44s cross-linking induced ERK1/2, JNK, c-jun, and IkappaBalpha phosphorylation only in the context of TCR engagement. No selectively CD44v6 associated transmembrane proteins were uncovered in EL4 cells. However, CD44v6, as opposed to CD44s, did not colocalise with the TCR/CD3 complex after CD3 cross-linking. Furthermore, a CD44-associated 85-kDa protein became hypophosphorylated only after CD44v6 cross-linking. Threonine hypophosphorylation of this protein coincided with the activation of MAP and SAP kinases, which was prohibited in the presence of a phosphatase inhibitor. Thus, CD44v6, distinct to CD44s, stimulates autonomously growth and IL-2 secretion of a thymoma line and rescues cells from apoptosis.
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PMID:CD44v6 promotes proliferation by persisting activation of MAP kinases. 1589 69

Hyaluronan exerts a variety of biological effects on cells including changes in cell migration, proliferation, and matrix metabolism. However, the signaling pathways associated with the action of hyaluronan on cells have not been clearly defined. In some cells, signaling is induced by the loss of cell-hyaluronan interactions. The goal of this study was to use hyaluronan oligosaccharides as a molecular tool to explore the effects of changes in cell-hyaluronan interactions and determine the underlying molecular events that become activated. In this study, hyaluronan oligosaccharides induced the loss of extracellular matrix proteoglycan and collagen from cultured slices of normal adult human articular cartilage. This loss was coincident with an increased expression of matrix metalloproteinase (MMP)-13. MMP-13 expression was also induced in articular chondrocytes by hyaluronan (HA) hexasaccharides but not by HA tetrasaccharides nor high molecular weight hyaluronan. MMP-13 promoter-reporter constructs in CD44-null COS-7 cells revealed that both CD44-dependent and CD44-independent events mediate the induction of MMP-13 by hyaluronan oligosaccharides. Electromobility gel shift assays demonstrated the activation of chondrocyte NFkappaB by hyaluronan oligosaccharides. NFkappaB activation was also documented in C-28/I2 immortalized human chondrocytes by luciferase promoter assays and phosphorylation of IKK-alpha/beta. The link between activation of NFkappaB and MMP-13 induction by HA oligosaccharides was further confirmed through the use of the NFkappaB inhibitor helenalin. Inhibition of MAP kinases also demonstrated the involvement of p38 MAP kinase in the hyaluronan oligosaccharide induction of MMP-13. Our findings suggest that hyaluronan-CD44 interactions affect matrix metabolism via activation of NFkappaB and p38 MAP kinase.
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PMID:Hyaluronan oligosaccharides induce matrix metalloproteinase 13 via transcriptional activation of NFkappaB and p38 MAP kinase in articular chondrocytes. 1664 33

The neurofibromatosis 2 (NF2) tumor suppressor protein merlin is commonly mutated in human benign brain tumors. The gene altered in NF2 was located on human chromosome 22q12 in 1993 and the encoded protein named merlin and schwannomin. Merlin has homology to ERM family proteins, ezrin, radixin, and moesin, within the protein 4.1 superfamily. In efforts to determine merlin function several groups have discovered 34 merlin interacting proteins, including ezrin, radixin, moesin, CD44, layilin, paxillin, actin, N-WASP, betaII-spectrin, microtubules, TRBP, eIF3c, PIKE, NHERF, MAP, RalGDS, RhoGDI, EG1/magicin, HEI10, HRS, syntenin, caspr/paranodin, DCC, NGB, CRM1/exportin, SCHIP1, MYPT-1-PP1delta, RIbeta, PKA, PAK (three types), calpain and Drosophila expanded. Many of the proteins that interact with the merlin N-terminal domain also bind ezrin, while other merlin interacting proteins do not bind other members of the ERM family. Merlin also interacts with itself. This review describes these proteins, their possible roles in NF2, and the resultant hypothesized merlin functions. Review of all of the merlin interacting proteins and functional consequences of losses of these interactions reveals multiple merlin actions in PI3-kinase, MAP kinase and small GTPase signaling pathways that might be targeted to inhibit the proliferation of NF2 tumors.
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PMID:The merlin interacting proteins reveal multiple targets for NF2 therapy. 1798 Jan 64

Early diagnosis of MAP infection is a pressing need to enable efficient intervention with the spread of MAP infection in herds. Hence, study of lymphocyte subsets and their expressed adhesion molecules could contribute in defining a distinct diagnostic marker (or markers) at the subclinical period of the infection that could in turn facilitate the development of effective diagnostic approach. In accordance with this objective, milk and blood samples were collected from two groups of cattle naturally infected with MAP and their corresponding negative controls. Group (C) comprised 3-4 year-old ELISA negative/PCR positive-cattle that were considered as subclinical seronegative low shedder group (early stage). Group (A) included 6-8 year-old ELISA positive-cattle, which were considered as a clinical seropositive group (late stage). Flow cytometry of B cells, CD8(+), CD4(+) and gammadelta cells and the adhesion molecules CD44(+), CD62L, LFA-1 and LPAM-1 indicated increase in CD4(+) and B cells levels, with higher levels in blood than milk of group A, and significant expression of CD44(+) in blood and milk and LPAM-1 in blood only. The CD8(+) cells count in milk was higher than blood in the late stage. The peculiar feature of the early stage (group C) was the high level of gammadelta cells in the blood and milk, with tendency to express high level of CD62L. Compelling evidence could support the assumption that the dominant gammadelta cells at early stage of MAP infection could be of CD8CD2(-)WC+1(+) phenotype. gammadelta cells appear as promising markers in defining early changes of MAP infection due to their important role in priming innate and cell mediated immunity. Possible utilization of these peculiar changes in the gammadelta cells level in the early diagnosis of MAP infection should be the subject of further research.
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PMID:The gammadelta cells as marker of non-seroconverted cattle naturally infected with Mycobacterium avium subspecies paratuberculosis. 1958 49

The A6 peptide (acetyl-KPSSPPEE-amino) has antitumor activity in the absence of significant adverse events in murine tumor models and clinical trials. A6 shares sequence homology with CD44, an adhesion receptor involved in metastasis that is also a marker of cancer stem cells and drug-resistant phenotypes. We investigated the mechanism of action of A6 by examining its effects on CD44 activity, cell migration, and metastasis. A6 inhibited the migration of a subset of ovarian and breast cancer cell lines, exhibiting IC(50) values of 5 to 110 nmol/L. The ability of A6 to inhibit migration in vitro correlated with CD44 expression. Immunopreciptation studies showed that CD44 binds A6 and that biotin-tagged A6 can be cross-linked to CD44. The binding of A6 altered the structure of CD44 such that it was no longer recognized by a monoclonal antibody to a specific epitope. Importantly, A6 potentiated the CD44-dependent adhesion of cancer cells to hyaluronic acid and activated CD44-mediated signaling, as evidenced by focal adhesion kinase and MAP/ERK kinase phosphorylation. In vivo, A6 (100 mg/kg delivered s.c. twice daily) reduced the number of lung foci generated by the i.v. injection of B16-F10 melanoma cells by 50% (P = 0.029 in an unpaired t test). We conclude that A6 potently blocks the migration of CD44-positive cells in vitro through an interaction with CD44 that alters its structure and activates CD44 to enhance ligand binding and downstream signaling. The concurrent ability of A6 to agonize the CD44 receptor suggests that CD44 activation may represent a novel strategy for inhibiting metastatic disease.
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PMID:A6 peptide activates CD44 adhesive activity, induces FAK and MEK phosphorylation, and inhibits the migration and metastasis of CD44-expressing cells. 2188 63

Carcinogen-induced oral cavity squamous cell carcinoma (OSCC) incurs significant morbidity and mortality and constitutes a global health challenge. To gain further insight into this disease, we generated cell line models from 7,12-dimethylbenz(a)anthracene-induced murine primary OSCC capable of tumor formation upon transplantation into immunocompetent wild-type mice. Whereas several cell lines grew rapidly and were capable of metastasis, some grew slowly and did not metastasize. Aggressively growing cell lines displayed ERK1/2 activation, which stimulated expression of CD44, a marker associated with epithelial to mesenchymal transition and putative cancer stem cells. MEK (MAP/ERK kinase) inhibition upstream of ERK1/2 decreased CD44 expression and promoter activity and reduced cell migration and invasion. Conversely, MEK1 activation enhanced CD44 expression and promoter activity, whereas CD44 attenuation reduced in vitro migration and in vivo tumor formation. Extending these findings to freshly resected human OSCC, we confirmed a strict relationship between ERK1/2 phosphorylation and CD44 expression. In summary, our findings identify CD44 as a critical target of ERK1/2 in promoting tumor aggressiveness and offer a preclinical proof-of-concept to target this pathway as a strategy to treat head and neck cancer.
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PMID:ERK1/2 regulation of CD44 modulates oral cancer aggressiveness. 2208 49

Tumor cell invasiveness is a critical challenge in the clinical management of glioma patients. In addition, there is accumulating evidence that current therapeutic modalities, including anti-angiogenic therapy and radiotherapy, can enhance glioma invasiveness. Glioma cell invasion is stimulated by both autocrine and paracrine factors that act on a large array of cell surface-bound receptors. Key signaling elements that mediate receptor-initiated signaling in the regulation of glioblastoma invasion are Rho family GTPases, including Rac, RhoA and Cdc42. These GTPases regulate cell morphology and actin dynamics and stimulate cell squeezing through the narrow extracellular spaces that are typical of the brain parenchyma. Transient attachment of cells to the extracellular matrix is also necessary for glioblastoma cell invasion. Interactions with extracellular matrix components are mediated by integrins that initiate diverse intracellular signalling pathways. Key signaling elements stimulated by integrins include PI3K, Akt, mTOR and MAP kinases. In order to detach from the tumor mass, glioma cells secrete proteolytic enzymes that cleave cell surface adhesion molecules, including CD44 and L1. Key proteases produced by glioma cells include uPA, ADAMs and MMPs. Increased understanding of the molecular mechanisms that control glioma cell invasion has led to the identification of molecular targets for therapeutic intervention in this devastating disease.
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PMID:Signaling determinants of glioma cell invasion. 2287 67


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