MET Signalling: Principles and Functions in Development, Organ Regeneration and Cancer

Overview

Journal Nat Rev Mol Cell Biol

Specialties Cell Biology
Molecular Biology

Date 2010 Nov 25

PMID 21102609

Citations 565

Authors

Livio Trusolino

Andrea Bertotti

Paolo M Comoglio

Affiliations

Soon will be listed here.

Abstract

The MET tyrosine kinase receptor (also known as the HGF receptor) promotes tissue remodelling, which underlies developmental morphogenesis, wound repair, organ homeostasis and cancer metastasis, by integrating growth, survival and migration cues in response to environmental stimuli or cell-autonomous perturbations. The versatility of MET-mediated biological responses is sustained by qualitative and quantitative signal modulation. Qualitative mechanisms include the engagement of dedicated signal transducers and the subcellular compartmentalization of MET signalling pathways, whereas quantitative regulation involves MET partnering with adaptor amplifiers or being degraded through the shedding of its extracellular domain or through intracellular ubiquitylation. Controlled activation of MET signalling can be exploited in regenerative medicine, whereas MET inhibition might slow down tumour progression.

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References

Potempa S, Ridley A . Activation of both MAP kinase and phosphatidylinositide 3-kinase by Ras is required for hepatocyte growth factor/scatter factor-induced adherens junction disassembly. Mol Biol Cell. 1998; 9(8):2185-200. PMC: 25472. DOI: 10.1091/mbc.9.8.2185. View

Michieli P, Mazzone M, Basilico C, Cavassa S, Sottile A, Naldini L . Targeting the tumor and its microenvironment by a dual-function decoy Met receptor. Cancer Cell. 2004; 6(1):61-73. DOI: 10.1016/j.ccr.2004.05.032. View

Trusolino L, Comoglio P . Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat Rev Cancer. 2002; 2(4):289-300. DOI: 10.1038/nrc779. View

Conrotto P, Corso S, Gamberini S, Comoglio P, Giordano S . Interplay between scatter factor receptors and B plexins controls invasive growth. Oncogene. 2004; 23(30):5131-7. DOI: 10.1038/sj.onc.1207650. View

Schafer M, Werner S . Cancer as an overhealing wound: an old hypothesis revisited. Nat Rev Mol Cell Biol. 2008; 9(8):628-38. DOI: 10.1038/nrm2455. View

Schmidt L, Duh F, Chen F, Kishida T, Glenn G, Choyke P . Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet. 1997; 16(1):68-73. DOI: 10.1038/ng0597-68. View

Huh C, Factor V, Sanchez A, Uchida K, Conner E, Thorgeirsson S . Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc Natl Acad Sci U S A. 2004; 101(13):4477-82. PMC: 384772. DOI: 10.1073/pnas.0306068101. View

Miyazawa K, Tsubouchi H, Naka D, Okigaki M, Arakaki N, Nakayama H . Molecular cloning and sequence analysis of cDNA for human hepatocyte growth factor. Biochem Biophys Res Commun. 1989; 163(2):967-73. DOI: 10.1016/0006-291x(89)92316-4. View

Comoglio P, Boccaccio C, Trusolino L . Interactions between growth factor receptors and adhesion molecules: breaking the rules. Curr Opin Cell Biol. 2003; 15(5):565-71. DOI: 10.1016/s0955-0674(03)00096-6. View

10.

Amit I, Citri A, Shay T, Lu Y, Katz M, Zhang F . A module of negative feedback regulators defines growth factor signaling. Nat Genet. 2007; 39(4):503-12. DOI: 10.1038/ng1987. View

11.

Maina F, Hilton M, Ponzetto C, Davies A, Klein R . Met receptor signaling is required for sensory nerve development and HGF promotes axonal growth and survival of sensory neurons. Genes Dev. 1998; 11(24):3341-50. PMC: 316818. DOI: 10.1101/gad.11.24.3341. View

12.

Scita G, Di Fiore P . The endocytic matrix. Nature. 2010; 463(7280):464-73. DOI: 10.1038/nature08910. View

13.

Ponzetto C, Bardelli A, Zhen Z, Maina F, dalla Zonca P, Giordano S . A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Cell. 1994; 77(2):261-71. DOI: 10.1016/0092-8674(94)90318-2. View

14.

Lai A, Abella J, Park M . Crosstalk in Met receptor oncogenesis. Trends Cell Biol. 2009; 19(10):542-51. DOI: 10.1016/j.tcb.2009.07.002. View

15.

Giordano S, Bardelli A, Zhen Z, Menard S, Ponzetto C, Comoglio P . A point mutation in the MET oncogene abrogates metastasis without affecting transformation. Proc Natl Acad Sci U S A. 1998; 94(25):13868-72. PMC: 28399. DOI: 10.1073/pnas.94.25.13868. View

16.

Kobayashi T, Honke K, Miyazaki T, Matsumoto K, Nakamura T, ISHIZUKA I . Hepatocyte growth factor specifically binds to sulfoglycolipids. J Biol Chem. 1994; 269(13):9817-21. View

17.

Mars W, Zarnegar R, Michalopoulos G . Activation of hepatocyte growth factor by the plasminogen activators uPA and tPA. Am J Pathol. 1993; 143(3):949-58. PMC: 1887222. View

18.

Weidner K, Di Cesare S, Sachs M, Brinkmann V, Behrens J, Birchmeier W . Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis. Nature. 1996; 384(6605):173-6. DOI: 10.1038/384173a0. View

19.

Smolen G, Sordella R, Muir B, Mohapatra G, Barmettler A, Archibald H . Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752. Proc Natl Acad Sci U S A. 2006; 103(7):2316-21. PMC: 1413705. DOI: 10.1073/pnas.0508776103. View

20.

Coltella N, Rasola A, Nano E, Bardella C, Fassetta M, Filigheddu N . p38 MAPK turns hepatocyte growth factor to a death signal that commits ovarian cancer cells to chemotherapy-induced apoptosis. Int J Cancer. 2006; 118(12):2981-90. DOI: 10.1002/ijc.21766. View