Mutant K-Ras activation of the proapoptotic MST2 pathway is antagonized by wild-type K-Ras.
K-Ras mutations are frequent in colorectal cancer (CRC), albeit K-Ras is the only Ras isoform that can elicit apoptosis. Here, we show that mutant K-Ras directly binds to the tumor suppressor RASSF1A to activate the apoptotic MST2-LATS1 pathway. In this pathway LATS1 binds to and sequesters the ubiq...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
2011
|
| _version_ | 1797073773121241088 |
|---|---|
| author | Matallanas, D Romano, D Al-Mulla, F O'Neill, E Al-Ali, W Crespo, P Doyle, B Nixon, C Sansom, O Drosten, M Barbacid, M Kolch, W |
| author_facet | Matallanas, D Romano, D Al-Mulla, F O'Neill, E Al-Ali, W Crespo, P Doyle, B Nixon, C Sansom, O Drosten, M Barbacid, M Kolch, W |
| author_sort | Matallanas, D |
| collection | OXFORD |
| description | K-Ras mutations are frequent in colorectal cancer (CRC), albeit K-Ras is the only Ras isoform that can elicit apoptosis. Here, we show that mutant K-Ras directly binds to the tumor suppressor RASSF1A to activate the apoptotic MST2-LATS1 pathway. In this pathway LATS1 binds to and sequesters the ubiquitin ligase Mdm2 causing stabilization of the tumor suppressor p53 and apoptosis. However, mutant Ras also stimulates autocrine activation of the EGF receptor (EGFR) which counteracts mutant K-Ras-induced apoptosis. Interestingly, this protection requires the wild-type K-Ras allele, which inhibits the MST2 pathway in part via AKT activation. Confirming the pathophysiological relevance of the molecular findings, we find a negative correlation between K-Ras mutation and MST2 expression in human CRC patients and CRC mouse models. The small number of tumors with co-expression of mutant K-Ras and MST2 has elevated apoptosis rates. Thus, in CRC, mutant K-Ras transformation is supported by the wild-type allele. |
| first_indexed | 2024-03-06T23:26:50Z |
| format | Journal article |
| id | oxford-uuid:6aa75e18-2722-49d2-bb1d-9885435c5842 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:26:50Z |
| publishDate | 2011 |
| record_format | dspace |
| spelling | oxford-uuid:6aa75e18-2722-49d2-bb1d-9885435c58422022-03-26T18:58:50ZMutant K-Ras activation of the proapoptotic MST2 pathway is antagonized by wild-type K-Ras.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:6aa75e18-2722-49d2-bb1d-9885435c5842EnglishSymplectic Elements at Oxford2011Matallanas, DRomano, DAl-Mulla, FO'Neill, EAl-Ali, WCrespo, PDoyle, BNixon, CSansom, ODrosten, MBarbacid, MKolch, WK-Ras mutations are frequent in colorectal cancer (CRC), albeit K-Ras is the only Ras isoform that can elicit apoptosis. Here, we show that mutant K-Ras directly binds to the tumor suppressor RASSF1A to activate the apoptotic MST2-LATS1 pathway. In this pathway LATS1 binds to and sequesters the ubiquitin ligase Mdm2 causing stabilization of the tumor suppressor p53 and apoptosis. However, mutant Ras also stimulates autocrine activation of the EGF receptor (EGFR) which counteracts mutant K-Ras-induced apoptosis. Interestingly, this protection requires the wild-type K-Ras allele, which inhibits the MST2 pathway in part via AKT activation. Confirming the pathophysiological relevance of the molecular findings, we find a negative correlation between K-Ras mutation and MST2 expression in human CRC patients and CRC mouse models. The small number of tumors with co-expression of mutant K-Ras and MST2 has elevated apoptosis rates. Thus, in CRC, mutant K-Ras transformation is supported by the wild-type allele. |
| spellingShingle | Matallanas, D Romano, D Al-Mulla, F O'Neill, E Al-Ali, W Crespo, P Doyle, B Nixon, C Sansom, O Drosten, M Barbacid, M Kolch, W Mutant K-Ras activation of the proapoptotic MST2 pathway is antagonized by wild-type K-Ras. |
| title | Mutant K-Ras activation of the proapoptotic MST2 pathway is antagonized by wild-type K-Ras. |
| title_full | Mutant K-Ras activation of the proapoptotic MST2 pathway is antagonized by wild-type K-Ras. |
| title_fullStr | Mutant K-Ras activation of the proapoptotic MST2 pathway is antagonized by wild-type K-Ras. |
| title_full_unstemmed | Mutant K-Ras activation of the proapoptotic MST2 pathway is antagonized by wild-type K-Ras. |
| title_short | Mutant K-Ras activation of the proapoptotic MST2 pathway is antagonized by wild-type K-Ras. |
| title_sort | mutant k ras activation of the proapoptotic mst2 pathway is antagonized by wild type k ras |
| work_keys_str_mv | AT matallanasd mutantkrasactivationoftheproapoptoticmst2pathwayisantagonizedbywildtypekras AT romanod mutantkrasactivationoftheproapoptoticmst2pathwayisantagonizedbywildtypekras AT almullaf mutantkrasactivationoftheproapoptoticmst2pathwayisantagonizedbywildtypekras AT oneille mutantkrasactivationoftheproapoptoticmst2pathwayisantagonizedbywildtypekras AT alaliw mutantkrasactivationoftheproapoptoticmst2pathwayisantagonizedbywildtypekras AT crespop mutantkrasactivationoftheproapoptoticmst2pathwayisantagonizedbywildtypekras AT doyleb mutantkrasactivationoftheproapoptoticmst2pathwayisantagonizedbywildtypekras AT nixonc mutantkrasactivationoftheproapoptoticmst2pathwayisantagonizedbywildtypekras AT sansomo mutantkrasactivationoftheproapoptoticmst2pathwayisantagonizedbywildtypekras AT drostenm mutantkrasactivationoftheproapoptoticmst2pathwayisantagonizedbywildtypekras AT barbacidm mutantkrasactivationoftheproapoptoticmst2pathwayisantagonizedbywildtypekras AT kolchw mutantkrasactivationoftheproapoptoticmst2pathwayisantagonizedbywildtypekras |