c-Met activation leads to the establishment of a TGFβ-receptor regulatory network in bladder cancer progression
Treatment of muscle-invasive bladder cancer remains a major clinical challenge. Aberrant HGF/c-MET upregulation and activation is frequently observed in bladder cancer correlating with cancer progression and invasion. However, the mechanisms underlying HGF/c-MET-mediated invasion in bladder cancer r...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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NATURE PUBLISHING GROUP
2019
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| Subjects: | |
| Online Access: | http://hdl.handle.net/20.500.11937/77888 |
| _version_ | 1848763913284354048 |
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| author | Sim, W.J. Iyengar, P.V. Lama, D. Lui, S.K.L. Ng, H.C. Haviv-Shapira, L. Domany, E. Kappei, D. Tan, T.Z. Saie, A. Jaynes, P.W. Verma, C.S. Kumar, A.P. Rouanne, M. Ha, H.K. Radulescu, C. ten Dijke, P. Eichhorn, Pieter Thiery, J.P. |
| author_facet | Sim, W.J. Iyengar, P.V. Lama, D. Lui, S.K.L. Ng, H.C. Haviv-Shapira, L. Domany, E. Kappei, D. Tan, T.Z. Saie, A. Jaynes, P.W. Verma, C.S. Kumar, A.P. Rouanne, M. Ha, H.K. Radulescu, C. ten Dijke, P. Eichhorn, Pieter Thiery, J.P. |
| author_sort | Sim, W.J. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | Treatment of muscle-invasive bladder cancer remains a major clinical challenge. Aberrant HGF/c-MET upregulation and activation is frequently observed in bladder cancer correlating with cancer progression and invasion. However, the mechanisms underlying HGF/c-MET-mediated invasion in bladder cancer remains unknown. As part of a negative feedback loop SMAD7 binds to SMURF2 targeting the TGFβ receptor for degradation. Under these conditions, SMAD7 acts as a SMURF2 agonist by disrupting the intramolecular interactions within SMURF2. We demonstrate that HGF stimulates TGFβ signalling through c-SRC-mediated phosphorylation of SMURF2 resulting in loss of SMAD7 binding and enhanced SMURF2 C2-HECT interaction, inhibiting SMURF2 and enhancing TGFβ receptor stabilisation. This upregulation of the TGFβ pathway by HGF leads to TGFβ-mediated EMT and invasion. In vivo we show that TGFβ receptor inhibition prevents bladder cancer invasion. Furthermore, we make a rationale for the use of combinatorial TGFβ and MEK inhibitors for treatment of high-grade non-muscle-invasive bladder cancers. |
| first_indexed | 2025-11-14T11:11:01Z |
| format | Journal Article |
| id | curtin-20.500.11937-77888 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T11:11:01Z |
| publishDate | 2019 |
| publisher | NATURE PUBLISHING GROUP |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-778882020-04-24T07:06:30Z c-Met activation leads to the establishment of a TGFβ-receptor regulatory network in bladder cancer progression Sim, W.J. Iyengar, P.V. Lama, D. Lui, S.K.L. Ng, H.C. Haviv-Shapira, L. Domany, E. Kappei, D. Tan, T.Z. Saie, A. Jaynes, P.W. Verma, C.S. Kumar, A.P. Rouanne, M. Ha, H.K. Radulescu, C. ten Dijke, P. Eichhorn, Pieter Thiery, J.P. Science & Technology Multidisciplinary Sciences Science & Technology - Other Topics EPITHELIAL-MESENCHYMAL TRANSITIONS HEPATOCYTE GROWTH-FACTOR MOLECULAR-DYNAMICS UBIQUITIN LIGASE CARCINOMA-CELLS SCATTER FACTOR WW DOMAINS WEB SERVER SRC SMURF2 Treatment of muscle-invasive bladder cancer remains a major clinical challenge. Aberrant HGF/c-MET upregulation and activation is frequently observed in bladder cancer correlating with cancer progression and invasion. However, the mechanisms underlying HGF/c-MET-mediated invasion in bladder cancer remains unknown. As part of a negative feedback loop SMAD7 binds to SMURF2 targeting the TGFβ receptor for degradation. Under these conditions, SMAD7 acts as a SMURF2 agonist by disrupting the intramolecular interactions within SMURF2. We demonstrate that HGF stimulates TGFβ signalling through c-SRC-mediated phosphorylation of SMURF2 resulting in loss of SMAD7 binding and enhanced SMURF2 C2-HECT interaction, inhibiting SMURF2 and enhancing TGFβ receptor stabilisation. This upregulation of the TGFβ pathway by HGF leads to TGFβ-mediated EMT and invasion. In vivo we show that TGFβ receptor inhibition prevents bladder cancer invasion. Furthermore, we make a rationale for the use of combinatorial TGFβ and MEK inhibitors for treatment of high-grade non-muscle-invasive bladder cancers. 2019 Journal Article http://hdl.handle.net/20.500.11937/77888 10.1038/s41467-019-12241-2 English NATURE PUBLISHING GROUP fulltext |
| spellingShingle | Science & Technology Multidisciplinary Sciences Science & Technology - Other Topics EPITHELIAL-MESENCHYMAL TRANSITIONS HEPATOCYTE GROWTH-FACTOR MOLECULAR-DYNAMICS UBIQUITIN LIGASE CARCINOMA-CELLS SCATTER FACTOR WW DOMAINS WEB SERVER SRC SMURF2 Sim, W.J. Iyengar, P.V. Lama, D. Lui, S.K.L. Ng, H.C. Haviv-Shapira, L. Domany, E. Kappei, D. Tan, T.Z. Saie, A. Jaynes, P.W. Verma, C.S. Kumar, A.P. Rouanne, M. Ha, H.K. Radulescu, C. ten Dijke, P. Eichhorn, Pieter Thiery, J.P. c-Met activation leads to the establishment of a TGFβ-receptor regulatory network in bladder cancer progression |
| title | c-Met activation leads to the establishment of a TGFβ-receptor regulatory network in bladder cancer progression |
| title_full | c-Met activation leads to the establishment of a TGFβ-receptor regulatory network in bladder cancer progression |
| title_fullStr | c-Met activation leads to the establishment of a TGFβ-receptor regulatory network in bladder cancer progression |
| title_full_unstemmed | c-Met activation leads to the establishment of a TGFβ-receptor regulatory network in bladder cancer progression |
| title_short | c-Met activation leads to the establishment of a TGFβ-receptor regulatory network in bladder cancer progression |
| title_sort | c-met activation leads to the establishment of a tgfβ-receptor regulatory network in bladder cancer progression |
| topic | Science & Technology Multidisciplinary Sciences Science & Technology - Other Topics EPITHELIAL-MESENCHYMAL TRANSITIONS HEPATOCYTE GROWTH-FACTOR MOLECULAR-DYNAMICS UBIQUITIN LIGASE CARCINOMA-CELLS SCATTER FACTOR WW DOMAINS WEB SERVER SRC SMURF2 |
| url | http://hdl.handle.net/20.500.11937/77888 |