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      Physiological Signaling and Structure of the HGF Receptor MET

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          Abstract

          The “hepatocyte growth factor” also known as “scatter factor”, is a multifunctional cytokine with the peculiar ability of simultaneously triggering epithelial cell proliferation, movement and survival. The combination of those proprieties results in the induction of an epithelial to mesenchymal transition in target cells, fundamental for embryogenesis but also exploited by tumor cells during metastatization. The hepatocyte growth factor receptor, MET, is a proto-oncogene and a prototypical transmembrane tyrosine kinase receptor. Inhere we discuss the MET molecular structure and the hepatocyte growth factor driven physiological signaling which coordinates epithelial proliferation, motility and morphogenesis.

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          CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis.

          Matilde Todaro, Miriam Gaggianesi, Veronica Catalano … (2014)
          Cancer stem cells drive tumor formation and metastasis, but how they acquire metastatic traits is not well understood. Here, we show that all colorectal cancer stem cells (CR-CSCs) express CD44v6, which is required for their migration and generation of metastatic tumors. CD44v6 expression is low in primary tumors but demarcated clonogenic CR-CSC populations. Cytokines hepatocyte growth factor (HGF), osteopontin (OPN), and stromal-derived factor 1α (SDF-1), secreted from tumor associated cells, increase CD44v6 expression in CR-CSCs by activating the Wnt/β-catenin pathway, which promotes migration and metastasis. CD44v6(-) progenitor cells do not give rise to metastatic lesions but, when treated with cytokines, acquire CD44v6 expression and metastatic capacity. Importantly, phosphatidylinositol 3-kinase (PI3K) inhibition selectively killed CD44v6 CR-CSCs and reduced metastatic growth. In patient cohorts, low levels of CD44v6 predict increased probability of survival. Thus, the metastatic process in colorectal cancer is initiated by CSCs through the expression of CD44v6, which is both a functional biomarker and therapeutic target. Copyright © 2014 Elsevier Inc. All rights reserved.
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            Molecular cloning and expression of human hepatocyte growth factor.

            T. Nakamura, T Nishizawa, M Hagiya … (1989)
            Hepatocyte growth factor (HGF) is the most potent mitogen for mature parenchymal hepatocytes in primary culture, and seems to be a hepatotrophic factor that acts as a trigger for liver regeneration after partial hepatectomy and liver injury. The partial purification and characterization of HGF have been reported. We have demonstrated that pure HGF from rat platelets is a new growth factor effective at concentrations as low as 1 ng ml-1. The effects of HGF and epidermal growth factor (EGF) are additive. The activity of HGF is not species-specific, although it does not stimulate growth in Swiss 3T3 fibroblasts. HGF has a relative molecular mass (Mr) of 82,000 and is a heterodimer composed of a large alpha-subunit of Mr 69,000 and a small beta-subunit of Mr 34,000. Here we report the amino-acid sequence of human HGF determined by complementary DNA cloning and the expression of biologically active human HGF from COS-1 cells transfected with cloned cDNA. The nucleotide sequence of the human HGF cDNA reveals that both alpha- and beta-chains are contained in a single open reading frame coding for a pre-pro precursor protein of 728 amino acids.
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              Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth

              G Gaudino, MF Di Renzo, L Naldini … (1992)
              Hepatocyte Growth Factor (HGF, also known as Scatter Factor) is a powerful mitogen or motility factor in different cells, acting through the tyrosine kinase receptor encoded by the MET protooncogene. Endothelial cells express the MET gene and expose at the cell surface the mature protein (p190MET) made of a 50 kD (alpha) subunit disulfide linked to a 145-kD (beta) subunit. HGF binding to endothelial cells identifies two sites with different affinities. The higher affinity binding site (Kd = 0.35 nM) corresponds to the p190MET receptor. Sub- nanomolar concentrations of HGF, but not of a recombinant inactive precursor, stimulate the receptor kinase activity, cell proliferation and motility. HGF induces repairs of a wound in endothelial cell monolayer. HGF stimulates the scatter of endothelial cells grown on three-dimensional collagen gels, inducing an elongated phenotype. In the rabbit cornea, highly purified HGF promotes neovascularization at sub-nanomolar concentrations. HGF lacks activities related to hemostasis-thrombosis, inflammation and endothelial cells accessory functions. These data show that HGF is an in vivo potent angiogenic factor and in vitro induces endothelial cells to proliferate and migrate.
              Article 0 comments Cited 188 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Zimmer Yitzhak: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): Biomedicines
                Journal ID (iso-abbrev): Biomedicines
                Journal ID (publisher-id): biomedicines
                Title: Biomedicines
                Publisher: MDPI
                ISSN (Electronic): 2227-9059
                Publication date (Electronic): 31 December 2014
                Publication date Collection: March 2015
                Volume: 3
                Issue: 1
                Pages: 1-31
                Affiliations
                [1 ]Department Translational Medicine, University Piemonte Orientale, via Solaroli 17, 28100 Novara, Italy
                [2 ]Università Vita-Salute San Raffaele, via Olgettina 58, 20132 Milano, Italy; E-Mail: andrea.graziani@ 123456med.unipmn.it
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: gianluca.baldanzi@ 123456med.unipmn.it ; Tel.: +39-0321-660527; Fax: +39-0321-620421.
                Article
                Publisher ID: biomedicines-03-00001
                DOI: 10.3390/biomedicines3010001
                PMC ID: 5344233
                PubMed ID: 28536396
                SO-VID: d4c5e470-47ea-4003-9ad9-0548e78f20ed
                Copyright © © 2014 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 30 September 2014
                Date accepted : 09 December 2014
                Categories
                Subject: Review

                Keywords: signaling pathways,tyrosine kinase receptor,protein–protein interaction,sh2 domain,post translational modification,signal transduction
                Data availability:
                Keywords: signaling pathways, tyrosine kinase receptor, protein–protein interaction, sh2 domain, post translational modification, signal transduction

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