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)

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), also known as hepatocyte growth factor-like, is a soluble cytokine that belongs to the family of the plasminogen-related growth factors (PRGFs). PRGFs are alpha/beta heterodimers that bind to transmembrane tyrosine kinase receptors. MSP was originally isolated as a chemotactic factor for peritoneal macrophages. Through binding to its receptor, encoded by the RON gene, it stimulates dissociation of epithelia and works as an inflammatory mediator by repressing the production of nitric oxide (NO). Here, we identify a novel role for MSP in the central nervous system. As a paradigm to analyze this function we chose the hypoglossal system of adult mice. We demonstrate in vivo that either administration of exogenous MSP or transplantation of MSP-producing cells at the proximal stump of the resected nerve is sufficient to prevent motoneuron atrophy upon axotomy. We also show that the MSP gene is expressed in the tongue, the target of the hypoglossal nerve, and that MSP induces biosynthesis of Ron receptor in the motoneuron somata. Finally, we show that MSP suppresses NO production in the injured hypoglossal nuclei. Together, these data suggest that MSP is a novel neurotrophic factor for cranial motoneurons and, by regulating the production of NO, may have a role in brain plasticity and regeneration.
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PMID:Macrophage stimulating protein is a novel neurotrophic factor. 1135 26

The cytokine Macrophage Stimulating 1 (MST1/MSP/Hepatocyte Growth Factor-Like) is a ligand of the Met-related MST1-Receptor (MST1R/RON). Although MST1-deficient mice are viable, MST1R is essential in mice before gastrulation for implantation, and is a known oncogene in man. Here I report the identification, sequence, chromosomal location and embryonic expression of a novel zebrafish orthologue, termed macrophage stimulating 1 (mst1). mst1 shows a striking restriction of expression to the dorsal side of the embryo prior to gastrulation, and as gastrulation and somitogenesis proceed is expressed sequentially in the presumptive neurectoderm, the notochord, the somites, endodermal cells and in the syncytial yolk. This dynamic pattern is largely conserved in tetrapod vertebrates, suggesting that the appearance of MST1, may have played an early role in the evolution of the vertebrate body plan.
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PMID:Identification and developmental expression of a macrophage stimulating 1/ hepatocyte growth factor-like 1 orthologue in the zebrafish. 1276 15

The prostate transglutaminase, TGase-4, is a member of the transglutaminase family and is uniquely expressed in the prostate gland. The function of the protein is largely unknown, although an influence on cell motility and adhesion has been indicated. The present study investigated the impact of the differential expression of TGase-4 in human prostate cancer cells on RON, the hepatocyte growth factor-like/macrophage-stimulating protein (HGF-L/MSP) receptor, mediated cellular functions. Using human prostate cancer cell lines and prostate tissues, we demonstrated that human TGase-4 had a high degree of co-localisation with RON, primarily at the cell periphery and cell-cell adhesion region. High levels of TGase-4 expression in CAHPV10 cells and in PC3 cells engineered to over-express TGase-4 were associated with significantly increased cell motility in response to HGF-L, a clear contrast to wild-type and control cells. Neutralising antibody to RON and rhHGFL/MSP had no further bearing on the increased motility in TGase-4 over-expressing cells, although they had profound effect on the control cells. Akt pathway inhibitor significantly diminished the effect induced by HGF-L in the cells. Finally, over-expression of TGase-4 in prostate cancer cells resulted in autophosphorylation of RON. It is concluded that TGase-4 expression is intrinsically linked to the activation of RON in prostate cancer cells and that this autoactivation of RON contributes to the increased cell motility in TGase-4 expressing cells.
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PMID:The prostate transglutaminase, TGase-4, coordinates with the HGFL/MSP-RON system in stimulating the migration of prostate cancer cells. 2059 68

Since the discovery of MSP (macrophage-stimulating protein; also known as MST1 and hepatocyte growth factor-like (HGFL)) as the ligand for the receptor tyrosine kinase RON (also known as MST1R) in the early 1990s, the roles of this signalling axis in cancer pathogenesis has been extensively studied in various model systems. Both in vitro and in vivo evidence has revealed that MSP-RON signalling is important for the invasive growth of different types of cancers. Currently, small-molecule inhibitors and antibodies blocking RON signalling are under investigation. Substantial responses have been achieved in human tumour xenograft models, laying the foundation for clinical validation. In this Review, we discuss recent advances that demonstrate the importance of MSP-RON signalling in cancer and its potential as a therapeutic target.
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PMID:MSP-RON signalling in cancer: pathogenesis and therapeutic potential. 2379 60

Although cytokine-based therapy is a promising tool to control the progression of esophageal cancer, low therapeutic responses largely compromise treatment efficacy through unidentified mechanisms. The goal of our study was to explore the roles of macrophage stimulating 1 (Mst1) and mitophagy in enhancing IL-24-based cytokine therapy in esophageal cancer. Our data demonstrated that IL-24 application promoted cancer death by inducing mitochondrial stress, as manifested by mitochondrial ROS overproduction, mitochondrial potential dissipation, cellular ATP deprivation and mitochondrial death activation. Overexpression of Mst1 enhanced IL-24-mediated mitochondrial damage and further augmented IL-24-induced death in esophageal cancer. Molecular investigations illustrated that the IL-24-activated mitochondrial response is accompanied by activation of mitophagy, a protective mechanism to attenuate mitochondrial damage. However, Mst1 overexpression inhibited mitophagy activity, which was achieved by inactivating the ERK-Mfn2 signaling pathway. The re-activation of mitophagy abolished the cancer-killing effects of Mst1 overexpression on esophageal cancer. Altogether, our data demonstrate that IL-24-related therapeutic resistance is associated with mitophagy activation. Mst1 overexpression inhibits mitophagy activity via suppressing the ERK-Mfn2 pathway, ultimately augmenting IL-24-inducd esophageal cancer death via enhanced mitochondrial stress.
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PMID:Overexpression of macrophage stimulating 1 enhances the anti-tumor effects of IL-24 in esophageal cancer via inhibiting ERK-Mfn2 signaling-dependent mitophagy. 3098 Nov 8