Liprin‐α1 contributes to oncogenic MAPK signaling by counteracting ERK activity
PTPRF interacting protein alpha 1 (PPFIA1) encodes for liprin‐α1, a member of the leukocyte common antigen–related protein tyrosine phosphatase (LAR‐RPTPs)‐interacting protein family. Liprin‐α1 localizes to adhesive and invasive structures in the periphery of cancer cells, where it modulates migrati...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2024-03-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.13593 |
| _version_ | 1827323327656493056 |
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| author | Henna Pehkonen Artemis Filippou Juho Väänänen Iida Lindfors Mira Vänttinen Philipp Ianevski Anne Mäkelä Pauliina Munne Juha Klefström Sanna Toppila‐Salmi Reidar Grénman Jaana Hagström Antti A. Mäkitie Piia‐Riitta Karhemo Outi Monni |
| author_facet | Henna Pehkonen Artemis Filippou Juho Väänänen Iida Lindfors Mira Vänttinen Philipp Ianevski Anne Mäkelä Pauliina Munne Juha Klefström Sanna Toppila‐Salmi Reidar Grénman Jaana Hagström Antti A. Mäkitie Piia‐Riitta Karhemo Outi Monni |
| author_sort | Henna Pehkonen |
| collection | DOAJ |
| description | PTPRF interacting protein alpha 1 (PPFIA1) encodes for liprin‐α1, a member of the leukocyte common antigen–related protein tyrosine phosphatase (LAR‐RPTPs)‐interacting protein family. Liprin‐α1 localizes to adhesive and invasive structures in the periphery of cancer cells, where it modulates migration and invasion in head and neck squamous cell carcinoma (HNSCC) and breast cancer. To study the possible role of liprin‐α1 in anticancer drug responses, we screened a library of oncology compounds in cell lines with high endogenous PPFIA1 expression. The compounds with the highest differential responses between high PPFIA1‐expressing and silenced cells across cell lines were inhibitors targeting mitogen‐activated protein kinase kinase (MEK)/extracellular signal‐regulated kinases (ERK) signaling. KRAS proto‐oncogene, GTPase (KRAS)‐mutated MDA‐MB‐231 cells were more resistant to trametinib upon PPFIA1 knockdown compared with control cells. In contrast, liprin‐α1‐depleted HNSCC cells with low RAS activity showed a context‐dependent response to MEK/ERK inhibitors. Importantly, we showed that liprin‐α1 depletion leads to increased p‐ERK1/2 levels in all our studied cell lines independent of KRAS mutational status, suggesting a role of liprin‐α1 in the regulation of MAPK oncogenic signaling. Furthermore, liprin‐α1 depletion led to more pronounced redistribution of RAS proteins to the cell membrane. Our data suggest that liprin‐α1 is an important contributor to oncogenic RAS/MAPK signaling, and the status of liprin‐α1 may assist in predicting drug responses in cancer cells in a context‐dependent manner. |
| first_indexed | 2024-04-25T01:43:10Z |
| format | Article |
| id | doaj.art-5adbbe91f802423398c274eb66b71c64 |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-04-25T01:43:10Z |
| publishDate | 2024-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-5adbbe91f802423398c274eb66b71c642024-03-08T02:46:29ZengWileyMolecular Oncology1574-78911878-02612024-03-0118366267610.1002/1878-0261.13593Liprin‐α1 contributes to oncogenic MAPK signaling by counteracting ERK activityHenna Pehkonen0Artemis Filippou1Juho Väänänen2Iida Lindfors3Mira Vänttinen4Philipp Ianevski5Anne Mäkelä6Pauliina Munne7Juha Klefström8Sanna Toppila‐Salmi9Reidar Grénman10Jaana Hagström11Antti A. Mäkitie12Piia‐Riitta Karhemo13Outi Monni14Applied Tumor Genomics Research Program, Faculty of Medicine University of Helsinki FinlandApplied Tumor Genomics Research Program, Faculty of Medicine University of Helsinki FinlandApplied Tumor Genomics Research Program, Faculty of Medicine University of Helsinki FinlandApplied Tumor Genomics Research Program, Faculty of Medicine University of Helsinki FinlandApplied Tumor Genomics Research Program, Faculty of Medicine University of Helsinki FinlandInstitute for Molecular Medicine Finland (FIMM) University of Helsinki FinlandApplied Tumor Genomics Research Program, Faculty of Medicine University of Helsinki FinlandFinnish Cancer Institute, FICAN South Helsinki University Hospital & Translational Cancer Medicine, Medical Faculty University of Helsinki FinlandFinnish Cancer Institute, FICAN South Helsinki University Hospital & Translational Cancer Medicine, Medical Faculty University of Helsinki FinlandSkin and Allergy Hospital Helsinki University Hospital and University of Helsinki FinlandDepartment of Otorhinolaryngology‐Head and Neck Surgery University of Turku and Turku University Hospital FinlandDepartment of Pathology University of Helsinki and Helsinki University Hospital FinlandiCAN Digital Precision Cancer Medicine Flagship Helsinki FinlandApplied Tumor Genomics Research Program, Faculty of Medicine University of Helsinki FinlandApplied Tumor Genomics Research Program, Faculty of Medicine University of Helsinki FinlandPTPRF interacting protein alpha 1 (PPFIA1) encodes for liprin‐α1, a member of the leukocyte common antigen–related protein tyrosine phosphatase (LAR‐RPTPs)‐interacting protein family. Liprin‐α1 localizes to adhesive and invasive structures in the periphery of cancer cells, where it modulates migration and invasion in head and neck squamous cell carcinoma (HNSCC) and breast cancer. To study the possible role of liprin‐α1 in anticancer drug responses, we screened a library of oncology compounds in cell lines with high endogenous PPFIA1 expression. The compounds with the highest differential responses between high PPFIA1‐expressing and silenced cells across cell lines were inhibitors targeting mitogen‐activated protein kinase kinase (MEK)/extracellular signal‐regulated kinases (ERK) signaling. KRAS proto‐oncogene, GTPase (KRAS)‐mutated MDA‐MB‐231 cells were more resistant to trametinib upon PPFIA1 knockdown compared with control cells. In contrast, liprin‐α1‐depleted HNSCC cells with low RAS activity showed a context‐dependent response to MEK/ERK inhibitors. Importantly, we showed that liprin‐α1 depletion leads to increased p‐ERK1/2 levels in all our studied cell lines independent of KRAS mutational status, suggesting a role of liprin‐α1 in the regulation of MAPK oncogenic signaling. Furthermore, liprin‐α1 depletion led to more pronounced redistribution of RAS proteins to the cell membrane. Our data suggest that liprin‐α1 is an important contributor to oncogenic RAS/MAPK signaling, and the status of liprin‐α1 may assist in predicting drug responses in cancer cells in a context‐dependent manner.https://doi.org/10.1002/1878-0261.13593drug screenhead and neck squamous cell carcinomaliprin‐α1MEK/ERK inhibitorMEK/ERK signaling pathwayRAS |
| spellingShingle | Henna Pehkonen Artemis Filippou Juho Väänänen Iida Lindfors Mira Vänttinen Philipp Ianevski Anne Mäkelä Pauliina Munne Juha Klefström Sanna Toppila‐Salmi Reidar Grénman Jaana Hagström Antti A. Mäkitie Piia‐Riitta Karhemo Outi Monni Liprin‐α1 contributes to oncogenic MAPK signaling by counteracting ERK activity Molecular Oncology drug screen head and neck squamous cell carcinoma liprin‐α1 MEK/ERK inhibitor MEK/ERK signaling pathway RAS |
| title | Liprin‐α1 contributes to oncogenic MAPK signaling by counteracting ERK activity |
| title_full | Liprin‐α1 contributes to oncogenic MAPK signaling by counteracting ERK activity |
| title_fullStr | Liprin‐α1 contributes to oncogenic MAPK signaling by counteracting ERK activity |
| title_full_unstemmed | Liprin‐α1 contributes to oncogenic MAPK signaling by counteracting ERK activity |
| title_short | Liprin‐α1 contributes to oncogenic MAPK signaling by counteracting ERK activity |
| title_sort | liprin α1 contributes to oncogenic mapk signaling by counteracting erk activity |
| topic | drug screen head and neck squamous cell carcinoma liprin‐α1 MEK/ERK inhibitor MEK/ERK signaling pathway RAS |
| url | https://doi.org/10.1002/1878-0261.13593 |
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