The Novel Phosphatase Domain Mutations Q171R and Y65S Switch PTEN from Tumor Suppressor to Oncogene
Phosphatase and tensin homolog deleted on chromosome 10, or PTEN, is a well-characterized tumor suppressor with both lipid and protein phosphatase activities. PTEN is often downregulated by epigenetic mechanisms such as hypermethylation, which leads to constitutive activation of the PI3K–Akt pathway...
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MDPI AG
2021-12-01
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| Online Access: | https://www.mdpi.com/2073-4409/10/12/3423 |
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| author | Jose Antonio Ma. G. Garrido Krizelle Mae M. Alcantara Joshua Miguel C. Danac Fidel Emmanuel C. Serrano Eva Maria Cutiongco-de la Paz Reynaldo L. Garcia |
| author_facet | Jose Antonio Ma. G. Garrido Krizelle Mae M. Alcantara Joshua Miguel C. Danac Fidel Emmanuel C. Serrano Eva Maria Cutiongco-de la Paz Reynaldo L. Garcia |
| author_sort | Jose Antonio Ma. G. Garrido |
| collection | DOAJ |
| description | Phosphatase and tensin homolog deleted on chromosome 10, or PTEN, is a well-characterized tumor suppressor with both lipid and protein phosphatase activities. PTEN is often downregulated by epigenetic mechanisms such as hypermethylation, which leads to constitutive activation of the PI3K–Akt pathway. Large datasets from next-generation sequencing, however, revealed that mutations in PTEN may not only hamper protein function but may also affect interactions with downstream effectors, leading to variable oncogenic readouts. Here, two novel PTEN mutations, Q171R and Y65S, identified in Filipino colorectal cancer patients, were phenotypically characterized in NIH3T3 and HCT116 cells, alongside the C124S canonical mutant and wild-type controls. The novel mutants increased cellular proliferation, resistance to apoptosis and migratory capacity. They induced gross morphological changes including cytoplasmic shrinkage, increased cellular protrusions and extensive cytoskeletal reorganization. The mutants also induced a modest increase in Akt phosphorylation. Further mechanistic studies will help determine the differential oncogenic potencies of these mutants, and resolve whether the structural constraints imposed by the mutations may have altered associations with downstream effectors. |
| first_indexed | 2024-03-10T04:26:22Z |
| format | Article |
| id | doaj.art-f793b67c3f6649d1b0654c17a637071e |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T04:26:22Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-f793b67c3f6649d1b0654c17a637071e2023-11-23T07:37:35ZengMDPI AGCells2073-44092021-12-011012342310.3390/cells10123423The Novel Phosphatase Domain Mutations Q171R and Y65S Switch PTEN from Tumor Suppressor to OncogeneJose Antonio Ma. G. Garrido0Krizelle Mae M. Alcantara1Joshua Miguel C. Danac2Fidel Emmanuel C. Serrano3Eva Maria Cutiongco-de la Paz4Reynaldo L. Garcia5Disease Molecular Biology and Epigenetics Laboratory, National Institute of Molecular Biology and Biotechnology, University of the Philippines Diliman, Quezon City 1101, PhilippinesDisease Molecular Biology and Epigenetics Laboratory, National Institute of Molecular Biology and Biotechnology, University of the Philippines Diliman, Quezon City 1101, PhilippinesDisease Molecular Biology and Epigenetics Laboratory, National Institute of Molecular Biology and Biotechnology, University of the Philippines Diliman, Quezon City 1101, PhilippinesDisease Molecular Biology and Epigenetics Laboratory, National Institute of Molecular Biology and Biotechnology, University of the Philippines Diliman, Quezon City 1101, PhilippinesInstitute of Human Genetics, University of the Philippines Manila, Manila 1000, PhilippinesDisease Molecular Biology and Epigenetics Laboratory, National Institute of Molecular Biology and Biotechnology, University of the Philippines Diliman, Quezon City 1101, PhilippinesPhosphatase and tensin homolog deleted on chromosome 10, or PTEN, is a well-characterized tumor suppressor with both lipid and protein phosphatase activities. PTEN is often downregulated by epigenetic mechanisms such as hypermethylation, which leads to constitutive activation of the PI3K–Akt pathway. Large datasets from next-generation sequencing, however, revealed that mutations in PTEN may not only hamper protein function but may also affect interactions with downstream effectors, leading to variable oncogenic readouts. Here, two novel PTEN mutations, Q171R and Y65S, identified in Filipino colorectal cancer patients, were phenotypically characterized in NIH3T3 and HCT116 cells, alongside the C124S canonical mutant and wild-type controls. The novel mutants increased cellular proliferation, resistance to apoptosis and migratory capacity. They induced gross morphological changes including cytoplasmic shrinkage, increased cellular protrusions and extensive cytoskeletal reorganization. The mutants also induced a modest increase in Akt phosphorylation. Further mechanistic studies will help determine the differential oncogenic potencies of these mutants, and resolve whether the structural constraints imposed by the mutations may have altered associations with downstream effectors.https://www.mdpi.com/2073-4409/10/12/3423PTENcolorectal cancerEGFR pathwaytumor suppressor |
| spellingShingle | Jose Antonio Ma. G. Garrido Krizelle Mae M. Alcantara Joshua Miguel C. Danac Fidel Emmanuel C. Serrano Eva Maria Cutiongco-de la Paz Reynaldo L. Garcia The Novel Phosphatase Domain Mutations Q171R and Y65S Switch PTEN from Tumor Suppressor to Oncogene Cells PTEN colorectal cancer EGFR pathway tumor suppressor |
| title | The Novel Phosphatase Domain Mutations Q171R and Y65S Switch PTEN from Tumor Suppressor to Oncogene |
| title_full | The Novel Phosphatase Domain Mutations Q171R and Y65S Switch PTEN from Tumor Suppressor to Oncogene |
| title_fullStr | The Novel Phosphatase Domain Mutations Q171R and Y65S Switch PTEN from Tumor Suppressor to Oncogene |
| title_full_unstemmed | The Novel Phosphatase Domain Mutations Q171R and Y65S Switch PTEN from Tumor Suppressor to Oncogene |
| title_short | The Novel Phosphatase Domain Mutations Q171R and Y65S Switch PTEN from Tumor Suppressor to Oncogene |
| title_sort | novel phosphatase domain mutations q171r and y65s switch pten from tumor suppressor to oncogene |
| topic | PTEN colorectal cancer EGFR pathway tumor suppressor |
| url | https://www.mdpi.com/2073-4409/10/12/3423 |
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