Mutant p53 enhances MET trafficking and signalling to drive cell scattering and invasion
Tumour-derived mutant p53 proteins promote invasion, in part, by enhancing Rab coupling protein (RCP)-dependent receptor recycling. Here we identified MET as an RCP-binding protein and showed that mutant p53 promoted MET recycling. Mutant p53-expressing cells were more sensitive to hepatocyte growth...
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| Veröffentlicht in: | Oncogene 2013-03, Vol.32 (10), p.1252-1265 |
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| creator | Muller, P A J Trinidad, A G Timpson, P Morton, J P Zanivan, S van den Berghe, P V E Nixon, C Karim, S A Caswell, P T Noll, J E Coffill, C R Lane, D P Sansom, O J Neilsen, P M Norman, J C Vousden, K H |
| description | Tumour-derived mutant p53 proteins promote invasion, in part, by enhancing Rab coupling protein (RCP)-dependent receptor recycling. Here we identified MET as an RCP-binding protein and showed that mutant p53 promoted MET recycling. Mutant p53-expressing cells were more sensitive to hepatocyte growth factor, the ligand for MET, leading to enhanced MET signalling, invasion and cell scattering that was dependent on both MET and RCP. In cells expressing the p53 family member TAp63, inhibition of TAp63 also lead to cell scattering and MET-dependent invasion. However, in cells that express very low levels of TAp63, the ability of mutant p53 to promote MET-dependent cell scattering was independent of TAp63. Taken together, our data show that mutant p53 can enhance MET signalling to promote cell scattering and invasion through both TAp63-dependent and -independent mechanisms. MET has a predominant role in metastatic progression and the identification of mechanisms through which mutations in p53 can drive MET signalling may help to identify and direct therapy. |
| doi_str_mv | 10.1038/onc.2012.148 |
| format | Article |
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Here we identified MET as an RCP-binding protein and showed that mutant p53 promoted MET recycling. Mutant p53-expressing cells were more sensitive to hepatocyte growth factor, the ligand for MET, leading to enhanced MET signalling, invasion and cell scattering that was dependent on both MET and RCP. In cells expressing the p53 family member TAp63, inhibition of TAp63 also lead to cell scattering and MET-dependent invasion. However, in cells that express very low levels of TAp63, the ability of mutant p53 to promote MET-dependent cell scattering was independent of TAp63. Taken together, our data show that mutant p53 can enhance MET signalling to promote cell scattering and invasion through both TAp63-dependent and -independent mechanisms. MET has a predominant role in metastatic progression and the identification of mechanisms through which mutations in p53 can drive MET signalling may help to identify and direct therapy.</description><identifier>ISSN: 0950-9232</identifier><identifier>ISSN: 1476-5594</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/onc.2012.148</identifier><identifier>PMID: 22580601</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/67/322 ; 631/80/84/2336 ; 631/80/86 ; Animals ; Apoptosis ; Cancer cells ; Carcinoma, Non-Small-Cell Lung - genetics ; Carcinoma, Non-Small-Cell Lung - metabolism ; Carcinoma, Non-Small-Cell Lung - pathology ; Cell adhesion & migration ; Cell Biology ; Cell Movement ; Colonic Neoplasms - genetics ; Colonic Neoplasms - metabolism ; Colonic Neoplasms - pathology ; HCT116 Cells ; HT29 Cells ; Human Genetics ; Humans ; Internal Medicine ; Lung Neoplasms - genetics ; Lung Neoplasms - metabolism ; Lung Neoplasms - pathology ; Medicine ; Medicine & Public Health ; Metastasis ; Mice ; Mutation ; Neoplasm Invasiveness ; Oncology ; Original ; original-article ; Phosphorylation ; Proteins ; Proto-Oncogene Proteins c-met - genetics ; Proto-Oncogene Proteins c-met - metabolism ; Signal Transduction ; Transcription Factors - metabolism ; Transfection ; Tumor proteins ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism ; Tumor Suppressor Proteins - metabolism ; Tumors</subject><ispartof>Oncogene, 2013-03, Vol.32 (10), p.1252-1265</ispartof><rights>The Author(s) 2013</rights><rights>COPYRIGHT 2013 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Mar 7, 2013</rights><rights>Copyright © 2013 Macmillan Publishers Limited 2013 Macmillan Publishers Limited</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c550t-24eaa9bfad4b7e51e22fa8991c10a253d70515ca180250e85ce9c21a483e4ab3</citedby><cites>FETCH-LOGICAL-c550t-24eaa9bfad4b7e51e22fa8991c10a253d70515ca180250e85ce9c21a483e4ab3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/onc.2012.148$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/onc.2012.148$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22580601$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Muller, P A J</creatorcontrib><creatorcontrib>Trinidad, A G</creatorcontrib><creatorcontrib>Timpson, P</creatorcontrib><creatorcontrib>Morton, J P</creatorcontrib><creatorcontrib>Zanivan, S</creatorcontrib><creatorcontrib>van den Berghe, P V E</creatorcontrib><creatorcontrib>Nixon, C</creatorcontrib><creatorcontrib>Karim, S A</creatorcontrib><creatorcontrib>Caswell, P T</creatorcontrib><creatorcontrib>Noll, J E</creatorcontrib><creatorcontrib>Coffill, C R</creatorcontrib><creatorcontrib>Lane, D P</creatorcontrib><creatorcontrib>Sansom, O J</creatorcontrib><creatorcontrib>Neilsen, P M</creatorcontrib><creatorcontrib>Norman, J C</creatorcontrib><creatorcontrib>Vousden, K H</creatorcontrib><title>Mutant p53 enhances MET trafficking and signalling to drive cell scattering and invasion</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Tumour-derived mutant p53 proteins promote invasion, in part, by enhancing Rab coupling protein (RCP)-dependent receptor recycling. Here we identified MET as an RCP-binding protein and showed that mutant p53 promoted MET recycling. Mutant p53-expressing cells were more sensitive to hepatocyte growth factor, the ligand for MET, leading to enhanced MET signalling, invasion and cell scattering that was dependent on both MET and RCP. In cells expressing the p53 family member TAp63, inhibition of TAp63 also lead to cell scattering and MET-dependent invasion. However, in cells that express very low levels of TAp63, the ability of mutant p53 to promote MET-dependent cell scattering was independent of TAp63. Taken together, our data show that mutant p53 can enhance MET signalling to promote cell scattering and invasion through both TAp63-dependent and -independent mechanisms. MET has a predominant role in metastatic progression and the identification of mechanisms through which mutations in p53 can drive MET signalling may help to identify and direct therapy.</description><subject>631/67/322</subject><subject>631/80/84/2336</subject><subject>631/80/86</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Cancer cells</subject><subject>Carcinoma, Non-Small-Cell Lung - genetics</subject><subject>Carcinoma, Non-Small-Cell Lung - metabolism</subject><subject>Carcinoma, Non-Small-Cell Lung - pathology</subject><subject>Cell adhesion & migration</subject><subject>Cell Biology</subject><subject>Cell Movement</subject><subject>Colonic Neoplasms - genetics</subject><subject>Colonic Neoplasms - metabolism</subject><subject>Colonic Neoplasms - pathology</subject><subject>HCT116 Cells</subject><subject>HT29 Cells</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Lung Neoplasms - genetics</subject><subject>Lung Neoplasms - 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Here we identified MET as an RCP-binding protein and showed that mutant p53 promoted MET recycling. Mutant p53-expressing cells were more sensitive to hepatocyte growth factor, the ligand for MET, leading to enhanced MET signalling, invasion and cell scattering that was dependent on both MET and RCP. In cells expressing the p53 family member TAp63, inhibition of TAp63 also lead to cell scattering and MET-dependent invasion. However, in cells that express very low levels of TAp63, the ability of mutant p53 to promote MET-dependent cell scattering was independent of TAp63. Taken together, our data show that mutant p53 can enhance MET signalling to promote cell scattering and invasion through both TAp63-dependent and -independent mechanisms. MET has a predominant role in metastatic progression and the identification of mechanisms through which mutations in p53 can drive MET signalling may help to identify and direct therapy.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>22580601</pmid><doi>10.1038/onc.2012.148</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 631/67/322 631/80/84/2336 631/80/86 Animals Apoptosis Cancer cells Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - metabolism Carcinoma, Non-Small-Cell Lung - pathology Cell adhesion & migration Cell Biology Cell Movement Colonic Neoplasms - genetics Colonic Neoplasms - metabolism Colonic Neoplasms - pathology HCT116 Cells HT29 Cells Human Genetics Humans Internal Medicine Lung Neoplasms - genetics Lung Neoplasms - metabolism Lung Neoplasms - pathology Medicine Medicine & Public Health Metastasis Mice Mutation Neoplasm Invasiveness Oncology Original original-article Phosphorylation Proteins Proto-Oncogene Proteins c-met - genetics Proto-Oncogene Proteins c-met - metabolism Signal Transduction Transcription Factors - metabolism Transfection Tumor proteins Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism Tumor Suppressor Proteins - metabolism Tumors |
| title | Mutant p53 enhances MET trafficking and signalling to drive cell scattering and invasion |
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