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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Macrophage-stimulating protein (MSP) is an 80-kD serum protein with homology to hepatocyte growth factor (HGF). Its receptor, RON tyrosine kinase, is a new member of the HGF receptor family. The MSP-RON signaling pathway has been implicated in the functional regulation of mononuclear phagocytes. However, the function of this pathway in other types of cells has not been elucidated. Here we show that in contrast to the HGF receptor, which was expressed at the basolateral surface, RON was localized at the apical surface of ciliated epithelia in the airways and oviduct. In addition, MSP was found in the bronchoalveolar space at biologically significant concentrations. MSP bound to RON on normal human bronchial epithelial cells with a high affinity (Kd = 0.5 nM) and induced autophosphorylation of RON. Activation of RON by MSP led to a significant increase in ciliary beat frequency of human nasal cilia. These findings indicate that the ciliated epithelium of the mucociliary transport apparatus is a novel target of MSP. Ciliary motility is critical for mucociliary transport. Our findings suggest that the MSP-RON signaling pathway is a novel regulatory system of mucociliary function and might be involved in the host defense and fertilization.
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PMID:Role of macrophage-stimulating protein and its receptor, RON tyrosine kinase, in ciliary motility. 904 73

The HGF receptor family includes tyrosine kinases encoded by three oncogenes: MET, SEA and RON. The members of this gene family share a unique functional feature: they mediate cell dissociation and motility ('scattering') in physiological conditions, and invasiveness in their activated versions. The Met, Ron and Sea receptors display a distinctive signal transduction behaviour. Unlike conventional growth factor receptors, their cytoplasmic tails contain a multifunctional docking site. Upon autophosphorylation, this sequence simultaneously binds and activates multiple SH2-containing transducers, including Ras and PI 3-kinase. A deregulated activation of this 'supersite' triggers a dramatic pleiotropic signal which is responsible for invasive cell growth.
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PMID:The HGF receptor family: unconventional signal transducers for invasive cell growth. 913 79

Transient pulmonary neuroendocrine cell hyperplasia and non-neuroendocrine lung tumors develop in nitrosaminetreated hamsters, which we hypothesized might modulate epithelial cell phenotype by expressing gene(s) homologous to human chromosome 3p gene(s) deleted in small cell carcinoma of the lung (SCLC). We differentially screened a chromosome 3 library using nitrosamine-treated versus normal hamster lung cDNAs and identified hepatocyte growth factor-like/macrophage-stimulating protein (HGFL/MSP) in injured lung. HGFL/MSP mRNA is low to undetectable in human SCLC and carcinoid tumors, but the HGFL/MSP tyrosine kinase receptor, RON, is present and functional on many of these neuroendocrine tumors. In H835, a pulmonary carcinoid cell line, and H187, a SCLC cell line, HGFL/ MSP induced adhesion/flattening and apoptosis. Using viable cell counts to assess proliferation after 14 d of treatment with HGFL/MSP, there is growth inhibition of H835 but not H187. Nitrosamine-treated hamsters also demonstrate pulmonary neuroendocrine cell apoptosis in situ during the same time period as expression of the endogenous HGFL/ MSP gene, immediately preceding the spontaneous regression of neuroendocrine cell hyperplasia. These observations suggest that HGFL/MSP might regulate neuroendocrine cell survival during preneoplastic lung injury, which could influence the ultimate tumor cell phenotype.
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PMID:Differential screening of a human chromosome 3 library identifies hepatocyte growth factor-like/macrophage-stimulating protein and its receptor in injured lung. Possible implications for neuroendocrine cell survival. 918 22

Macrophage stimulating protein (MSP) is a 78-kDa disulfide-linked heterodimer belonging to the plasminogen-related kringle protein family. MSP activates the RON receptor protein-tyrosine kinase, which results in cell migration, shape change, or proliferation. A structure-activity study of MSP was performed using pro-MSP, MSP, MSP alpha and beta chains, and a complex including the first two kringles and IgG Fc (MSP-NK2). Radioiodinated MSP and MSP beta chain both bound specifically to RON. The Kd of 1.4 nM for MSP beta chain is higher than the reported Kd range of 0.6-0.8 nM for MSP. Pro-MSP, MSP alpha chain, and MSP-NK2 did not bind. Only MSP stimulated RON autophosphorylation. Although the beta chain bound to RON and partially inhibited MSP-induced RON phosphorylation in kidney 293 cells, it did not induce RON phosphorylation. Pro-MSP, MSP alpha chain, or MSP-NK2 failed to activate RON, consistent with their inability to bind to the RON receptor. Functional studies showed that only MSP induced cell migration, and shape change in resident macrophages, and growth of murine keratinocytes. Our data indicate that the primary receptor binding domain is located in a region of the MSP beta chain, in contrast to structurally similar hepatocyte growth factor, in which the receptor binding site is in the alpha chain. However, full activation of RON requires binding of the complete MSP disulfide-linked alphabeta chain heterodimer.
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PMID:Macrophage stimulating protein (MSP) binds to its receptor via the MSP beta chain. 920 13

To analyze the molecular mechanisms of the proliferation and differentiation of hematopoietic cells, we have cloned PTKs from sorted stem cells. We discuss the expression and function of receptor tyrosine kinases, STK/RON, TIE, TEK and HTK which have been cloned from these cells. STK and its ligand, MSP contributed to the motility and phagocytosis of peritoneal macrophages and bone absorption of osteoclasts. Apoptosis was induced in an erythroid cell line by the binding of MSP(MacrophageStimulating Protein). TIE, TEK and HTK were interestingly expressed in the subpopulations of stem cells and related to the myeloid differentiation. These study will indicate the heterogeneity of stem cells and their diverse differentiation.
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PMID:Receptor tyrosine kinases involved in hematopoietic progenitor cells. 920 22

Hepatocyte growth factor (HGF) is the prototype of a family of structurally related soluble molecules, named scatter factors (SFs). These control a complex genetic programme leading to cell-dissociation, migration in the extracellular matrix, growth, acquisition of polarity and tubule formation. This programme is pivotal during the embryonic development of epithelial and some mesodermal-derived tissues. In the adult HGF sustains cell survival and regeneration. A structurally related molecule, originally identified as macrophage stimulating protein (MSP), triggers the same complex genetic programme in epithelial and neural cells. The receptors for HGF and MSP are the tyrosine kinases encoded by the homologous genes MET and RON. As a distinctive feature, these receptors act via a two-phosphotyrosine docking site, capable of concomitant activation of multiple intracellular transducers and signalling pathways. In a number of malignant tumours, MET and RON constitutively sustain the genetic programme of scattering, leading to invasive growth and metastatic phenotype. Four MET-related receptors have been recently identified (the SEX protein family). These molecules are predominantly expressed during development and are likely to mediate repelling cues between cells of different type.
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PMID:Control of invasive growth by hepatocyte growth factor (HGF) and related scatter factors. 924 8

Previously, we identified macrophage-stimulating protein (MSP) as being expressed during hamster lung injury induced by nitrosamine carcinogens. Transient, generalized epithelial-cell hyperplasia during the preneoplastic period, and eventually nonneuroendocrine (non-NE) lung tumors, are known to develop in these nitrosamine-treated hamsters. We wished to test the hypothesis that MSP and its tyrosine kinase receptor, RON, might represent an autocrine/paracrine system involved in the pathogenesis of human nonneuroendocrine lung tumors, the non-small-cell carcinomas (NSCLCs). We found that this occurred in a paracrine fashion in three of eight primary human NSCLCs that expressed messenger RNA (mRNA) for MSP at high levels in histologically normal lung adjacent to the tumor, but not in the primary tumor, together with mRNA for RON in both normal and tumor tissue. MSP and RON could also constitute an autocrine/paracrine system in human NSCLC cell lines: five of 16 cell lines (squamous and adenosquamous) expressed both MSP and RON; and an additional five of 16 cell lines expressed RON without detectable MSP. Although three cases of primary squamous-cell carcinomas expressed MSP (two of three in the tumor and one of three in nonneoplastic lung), mRNA for RON was not detectable in these cases. RON was functional in all tested RON mRNA-positive cell lines, with exogenous MSP inducing RON-mediated tyrosine phosphorylation. Treatment of a RON-positive adenosquamous carcinoma cell line with MSP additionally resulted in increased motility in a cell-migration assay, suggesting that MSP might promote cell migration of some NSCLCs. In conclusion, MSP and RON might represent an autocrine/paracrine system involved in the pathogenesis of lung cancer, although the nature of the biologic responses in different cell types might vary considerably.
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PMID:Macrophage-stimulating protein and its receptor in non-small-cell lung tumors: induction of receptor tyrosine phosphorylation and cell migration. 953 36

Constitutive activation of the RON gene, known to code for the tyrosine-kinase receptor for Macrophage Stimulating Protein (also known as Scatter Factor 2), has been shown to induce invasive-metastatic phenotype in vitro. As yet, nothing is known about the expression of this novel member of the MET-oncogene family in spontaneously occurring human cancers. Here we report that Ron is expressed at abnormally high levels in about 50% primary breast carcinomas (35/74 patients). Among these, the expression is increased more than 20-fold in 12 cases and the overexpressed protein is constitutively phosphorylated on tyrosine residues. Notably, Ron is only barely detectable in epithelial cells of the mammary gland, and its expression remains unchanged in benign breast lesions (including adenomas and papillomas). Overexpression was observed in different histotypic variants of carcinomas; it is associated with the disease at any stage and correlates with the post-menopausal status. In breast carcinoma cells grown in vitro, activation of the Ron receptor resulted in proliferation, migration and invasion through reconstituted basement membranes. Altogether, these data suggest a role for the RON gene in progression of human breast carcinomas to the invasive-metastatic phenotype.
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PMID:Overexpression of the RON gene in human breast carcinoma. 967 13

Immune and inflammatory responses must be rightly regulated to maintain a homoeostatic balance between an effective immune response and tissue damage to the host. NO is a principal mediator of many of the cytokine-inducible macrophage activities during a normal cell-mediated immune response. STK, the murine homologue of the human RON receptor tyrosine kinase, is expressed on murine resident peritoneal macrophages. The ligand for STK, macrophage-stimulating protein (MSP), is a serum protein that is activated by members of the coagulation cascade in response to tissue damage. In addition to its potential to induce chemotaxis and phagocytosis of C3bi-coated erythrocytes, MSP has an inhibitory effect on the production of NO by activated peritoneal macrophages in vitro. Here we demonstrate that peritoneal macrophages from mice lacking STK produce elevated levels of NO in response to interferon (IFN)-gamma in a dose-dependent manner, without the need for a co-stimulus. However, production of pro-inflammatory cytokines by activated macrophages from stk -/- mice is unaltered. In vivo, stk -/- mice exhibit increased inflammation in an IFN-gamma-mediated delayed-type hypersensitivity reaction and increased susceptibility to lipopolysaccharide (LPS)-induced endotoxic shock. Furthermore, the levels of NO in the serum of mice injected with LPS are significantly higher than those in control littermates. Nevertheless, the serum levels of IFN-gamma and the intermediate cytokines generated by the inflammatory response, which have previously been shown to play a role in septicaemic shock, do not differ significantly from controls. These data suggest that the STK receptor suppresses NO production, therefore ameliorating the potentially tissue-damaging effects of a cell-mediated immune response, through negative regulation of the IFN-gamma signalling pathway.
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PMID:Deregulated inflammatory response in mice lacking the STK/RON receptor tyrosine kinase. 968 Mar 29

Macrophage stimulating protein (MSP) exists in blood as inactive pro-MSP. Cleavage yields active MSP, the ligand for a membrane receptor (RON) that is expressed on keratinocytes as well as macrophages. Because both cells have roles in tissue injury, we looked for active MSP and expressed RON in wounds. Concentration of pro-MSP + MSP in wound exudates was in the range for optimal activity. Western blot showed that MSP comprised about half the total, in contrast to less than 10% of the total in blood plasma. The presence of MSP was attributed to an exudate pro-MSP convertase that had an inhibitor profile consistent with a trypsin-like serine protease. Exudate evoked morphologic changes in macrophages in vitro like that of MSP. Removal of this activity by an anti-MSP column shows that exudate stimulation of macrophages is due to MSP. RON was infrequently detected in normal skin. RON protein was markedly upregulated in burn wound epidermis and accessory structures, in proliferating cells or differentiated cells, or both. RON was also detected on macrophages and capillaries. Tissue injury leads to cleavage of pro-MSP to MSP, which has potential to act on keratinocytes, macrophages, and capillaries, all components of the wound healing response.
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PMID:Proteolytic cleavage and activation of pro-macrophage-stimulating protein and upregulation of its receptor in tissue injury. 976 35


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