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Thirty Years of Research on Met Receptor to Move a Biomarker from Bench to Bedside

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Thirty Years of Research on Met Receptor to Move a Biomarker from Bench to Bedside Published OnlineFirst November 19, 2014; DOI: 10.1158/0008-5472.CAN-14-1932 Cancer Review Research Thirty Years of Research on Met Receptor to Move a Biomarker from Bench to Bedside Alessandro Furlan1, Zoulika Kherrouche1,Remi Montagne1, Marie-Christine Copin1,2, and David Tulasne1 Abstract Met receptor tyrosine kinase was discovered in 1984 as an oncogene. Thirty years later, Met and its ligand hepatocyte growth factor/scatter factor are promising targets for the novel therapies developed to fight against cancers, with more than 240 clinical trials currently conducted. In this review, we offer to trace and highlight the most recent findings of the exemplary track record of research on Met receptor, which allowed moving this biomarker from bench to bedside. Indeed, three decades of basic research unravelled the structural basis of the ligand/receptor interaction and their complex downstream signaling network. During this period, animal models highlighted their crucial role in the development and homeostasis of epithelial organs. In parallel, involvement of Met in tumorigenesis was confirmed by the direct association of its deregulation to poor prognosis in numerous cancers. On the basis of these data, pharmaceutical companies developed many Met inhibitors, some of which are in phase III clinical trials. These impressive achievements should not detract from many questions that still remain, such as the precise Met signaling involvement in development or homeostasis of specific epithelial structures. In addition, the processes involving Met in resistance to current therapies or the appearance of resistances to Met-targeted therapies are far from being fully understood. Cancer Res; 74(23); 6737–44. Ó2014 AACR. Many phases II and III clinical trials are evaluating tar- TPR part of fusion proteins induces their constitutive dimer- geted therapies against Met in various types of carcinomas. ization and thus activation of Met kinase domain, resulting in It seems obvious nowadays that Met, like other receptor transforming activity. The HGF was isolated from the plasma of tyrosine kinases (RTK), is a promising target in our fight rats as a mitogen for cultured hepatocytes (2). Three years later, against cancers. However, a long way of basic and applied Stoker and colleagues identified a factor inducing epithelial research was necessary to place this RTK as a druggable cells scattering in fibroblast conditioned media so-called scat- actor of tumorigenesis. These multiple discoveries can be ter factor (SF; ref. 3). In 1991, HGF and SF were recognized as divided into three main steps: (i) Met physiologic role and its the same protein encoded by the same gene and inducing downstream signaling pathways, (ii) its involvement in similar biologic responses through binding to the Met receptor tumorigenesis, and (iii) the design and evaluation of the (4). targeted therapies against it. HGF/SF is synthesized as an inactive pro-HGF maturated by a proteolytic cleavage, leading to generation of an active Step 1: Met Physiologic Role and Its Downstream 90-kDa heterodimer consisting of an a and a b subunit bound Signaling Pathways by disulfide bridges. The a subunit includes an N-terminal (N) Discovery of HGF/SF and Met and four kringle (K1-K4) domains when the b subunit consists The Met receptor and the hepatocyte growth factor (HGF), of a serine protease homology (SPH) domain. Although SPH its high affinity ligand, were both discovered in 1984. Met was domain lacks enzymatic activity, a zymogen activator peptide characterized from the TPR-Met oncogene in the human selectively able to bind the activation pocket within the serine – – osteosarcoma cell line HOS treated by a carcinogen. This fusion protease like b-chain induces activation of pro-HGF depen- protein results from the rearrangement between the tpr dent Met signaling, suggesting that the protease-like structure gene and a novel gene, met, named in reference to the carcin- of HGF/SF plays a crucial role in its activation (5). Met is ogen used, the N-methyl-N'-nitro-N-nitrosoguanidine (1). The synthesized as a 170-kDa precursor matured into a hetero- dimeric receptor composed of an extracellular a subunit linked to a single-pass transmembrane b subunit by a disulfide 1CNRS UMR 8161, Institut de Biologie de Lille, Institut Pasteur de Lille, bond. The extracellular part of Met contains a N-terminal Universite de Lille 1, Universite de Lille 2, Lille, France. 2Institut de Patho- logie, CHR-U de Lille, Universite de Lille 2, Lille, France. SEMA domain (also found in semaphorins, axon guidance proteins) encompassing the a subunit and the first amino Corresponding Author: David Tulasne, CNRS UMR 8161, Institut de Biologie de Lille, Institut Pasteur de Lille, Universite de Lille 1, Universite acids of the b subunit, followed by a PSI domain (named from de Lille 2, SIRIC ONCOLille, FRE3642, 1 rue Pr Calmette, Lille 59021, its presence in plexins, semaphorins, and integrins) and four France. immunoglobulin-like domains called IPTs (Fig. 1A). The crystal doi: 10.1158/0008-5472.CAN-14-1932 structure of Met extracellular region, resolved in 2003, showed Ó2014 American Association for Cancer Research. the SEMA domain organized in a seven bladed b-propeller www.aacrjournals.org 6737 Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 2014 American Association for Cancer Research. Published OnlineFirst November 19, 2014; DOI: 10.1158/0008-5472.CAN-14-1932 Furlan et al. 1984: Discovery of Met and 2001: Met is ubiquitinated by Cbl in response hepatocyte growth factor (HGF) (1, 2) to HGF, leading to its degradation (19) 1987: Discovery of scatter factor (SF) (3) 2003: Resolution of Met structure (6) 1991: HGF and SF are the same growth 2004: Met is a dependence receptor factor, Met is their receptor (4) able to promote apoptosis (21) 1994: Met recruits signaling proteins through 2008: Internalization of Met participates its C-terminal multi-substrates binding site (7) to intracellular signaling (23) 1995: HGF/SF-Met are required for 2013: Met is required for epithelial organs embryonic development (10, 11) development and regeneration (12) AB CNeurons DLung Met Control Control ab SEMA downstream of Met downstream PSI IPT1 Conditional knock-out Conditional knock-out IPT2 IPT3 Physiological role and signaling pathways Physiological role IPT4 From Gherardi et al, PNAS, 2006 (8) Kinase From Lamballe et al, J From Calvi et al, Neuroscience, 2011 domain (13) PLOS Genetics, 2013 (12) 1984: TPR-Met fusion is transforming [1] 2004: Transgenic mice expressing mutated met develop carcinomas (31) 1996: Met overexpression is observed in many 2007–2013: met gene amplification leads to cancers and correlates with bad prognosis (32) resistance to targeted therapies against EGFR in lung and colorectal cancers (37, 38) 1997: Met mutations are associated to 2012: HGF secretion by tumor hereditary renal papillary carcinomas (29) microenvironment induces resistance to RAF inhibitors (36) met gene amplification, Met overexpression and phosphorylation in non small cell lung cancers EF G Involvement of Met in tumorigenesis Low expression High expression FISH; MET (green)/CEP7 (red) Met immunohistochemistry IHC; Phospho-Met Tyr 1234/1235 Blocking antibodies directed against H HGF/SF 2003: ATP mimetic inhibitors against HGF/SF or Met Met are developed (39, 40) NK2 2005: First clinical trials evaluating Antagonistic molecules of TKIs targeting Met Met or HGF/SF P P P P 2014: More than 240 clinical trials Met specific or multi-targets Tyrosine P P evaluating inhibitors against HGF/SF- Met-targeted therapies P P Met pathway are in progress Design and evaluation of kinase inhibitors (TKI) P P 1984 1994 2004 2014 6738 Cancer Res; 74(23) December 1, 2014 Cancer Research Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 2014 American Association for Cancer Research. Published OnlineFirst November 19, 2014; DOI: 10.1158/0008-5472.CAN-14-1932 Met from Bench to Bedside followed by stalk shaped PSI and IPT domains (6). The intra- impaired migration of myogenic precursors. In the last few cellular region contains the tyrosine kinase domain and a years, conditional Met knockout provided additional informa- C-terminal tail necessary to recruit signaling proteins following tion about its role in the formation of individual structures. Met activation by HGF/SF binding (7). Thus, Met invalidation in lung severely impairs formation of Met has two binding sites for HGF/SF: the IPT3 and IPT4 airspaces (12), and its extinction in central nervous system domains bind the N domain of HGF/SF and the SEMA domain induces loss of motor neurons innervating pectoral muscles binds SPH domain of HGF/SF. HGF/SF dimerizes via top and (Fig. 1C and D; ref. 13). In adult, Met is crucial for epithelial tail interactions of N and K1 domains, resulting in Met dimer- tissue homeostasis as conditional Met invalidation impairs ization (Fig. 1B; ref. 8). HGF/SF can also bind to sulphate regeneration of liver, kidney, or skin (14). On the contrary, glycoproteins, like heparins, which improve its oligomerization injury of kidney, spinal cord, or liver is followed by a rise in and thus Met dimerization. HGF/SF and its ectopic addition favors their regeneration. HGF/SF-Met involvement in development and tissue Met and downstream signaling pathways' activation homeostasis Met receptor signaling began to be described from the early Upon HGF/SF binding, Met can induce various biologic 1990s, shortly after its identification as the receptor for HGF/ responses, including proliferation and motility, at the origin SF. Met interaction with its ligand favors its dimerization and of their discovery, but also, survival, morphogenesis, angio- its autophosphorylation on two tyrosine residues in its cata- genesis, or neurite growth. All these effects are consistent with lytic domain (Y1234 et 1235). Other tyrosine residues located their role in vivo. Indeed, description of HGF/SF and Met outside the kinase domain are then phosphorylated, notably expression patterns suggested from early 1990s their impor- tyrosine 1003 in the juxtamembrane domain and tyrosines tance in formation and homeostasis of numerous tissues.
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