Biased signaling by mutant EGFR underlies dependence on PKCα in lung adenocarcinoma
Summary: Activating mutations in the epidermal growth factor receptor (EGFR) promote ligand-independent signaling; however, the mechanisms involved are poorly defined, and it is unknown whether this generates specific vulnerabilities. We previously observed robust expression of protein kinase Cα (PK...
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| Language: | English |
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Elsevier
2024-12-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124724013779 |
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| author | Mojtaba Sadeghi Mohamed F. Salama Sam B. Chiappone Amy Huang Andrew E. Resnick Manoj Kandpal Christopher J. Clarke John D. Haley Ramana V. Davuluri Yusuf A. Hannun |
| author_facet | Mojtaba Sadeghi Mohamed F. Salama Sam B. Chiappone Amy Huang Andrew E. Resnick Manoj Kandpal Christopher J. Clarke John D. Haley Ramana V. Davuluri Yusuf A. Hannun |
| author_sort | Mojtaba Sadeghi |
| collection | DOAJ |
| description | Summary: Activating mutations in the epidermal growth factor receptor (EGFR) promote ligand-independent signaling; however, the mechanisms involved are poorly defined, and it is unknown whether this generates specific vulnerabilities. We previously observed robust expression of protein kinase Cα (PKCα) in lung adenocarcinoma (LUAD) with mutant EGFR (mEGFR), which, unlike the activation of PKCα, is independent of mEGFR activity. Here, we identify a critical role for PKCα in anchorage-independent growth and survival of lung cancer cells with mEGFR. Mechanistically, signaling pathways initiated by mEGFR show a high preference for ligand-independent phosphorylation on Y992, resulting in biased activation and dependence on phospholipase-Cγ and PKCα. Moreover, through bioinformatic approaches, we find that mEGFR LUAD demonstrates a transcriptomic profile most similar to lung basal cells, which exhibit elevated levels of PKCα, suggesting that mEGFR tumors arise in cell types with high intrinsic levels of PKCα. Taken together, these findings explain the dependence of mEGFR on PKCα. |
| format | Article |
| id | doaj-art-ee7da34468014d86af2262d5cd62ca42 |
| institution | OA Journals |
| issn | 2211-1247 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-ee7da34468014d86af2262d5cd62ca422025-08-20T02:19:55ZengElsevierCell Reports2211-12472024-12-01431211502610.1016/j.celrep.2024.115026Biased signaling by mutant EGFR underlies dependence on PKCα in lung adenocarcinomaMojtaba Sadeghi0Mohamed F. Salama1Sam B. Chiappone2Amy Huang3Andrew E. Resnick4Manoj Kandpal5Christopher J. Clarke6John D. Haley7Ramana V. Davuluri8Yusuf A. Hannun9Department of Biochemistry, Stony Brook University, Stony Brook, NY 11794, USA; Stony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USAStony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USA; Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Department of Biochemistry, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, EgyptStony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USAStony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USAStony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USA; Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USACentre for Clinical and Translational Science, Rockefeller University, New York, NY 10065, USAStony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USA; Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USAStony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USA; Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USAStony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USA; Department of Biomedical Informatics, Stony Brook University, Stony Brook, NY 11794, USADepartment of Biochemistry, Stony Brook University, Stony Brook, NY 11794, USA; Stony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USA; Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Department of Veterans Affairs, Northport VA Medical Center, Northport, NY 11768, USA; Corresponding authorSummary: Activating mutations in the epidermal growth factor receptor (EGFR) promote ligand-independent signaling; however, the mechanisms involved are poorly defined, and it is unknown whether this generates specific vulnerabilities. We previously observed robust expression of protein kinase Cα (PKCα) in lung adenocarcinoma (LUAD) with mutant EGFR (mEGFR), which, unlike the activation of PKCα, is independent of mEGFR activity. Here, we identify a critical role for PKCα in anchorage-independent growth and survival of lung cancer cells with mEGFR. Mechanistically, signaling pathways initiated by mEGFR show a high preference for ligand-independent phosphorylation on Y992, resulting in biased activation and dependence on phospholipase-Cγ and PKCα. Moreover, through bioinformatic approaches, we find that mEGFR LUAD demonstrates a transcriptomic profile most similar to lung basal cells, which exhibit elevated levels of PKCα, suggesting that mEGFR tumors arise in cell types with high intrinsic levels of PKCα. Taken together, these findings explain the dependence of mEGFR on PKCα.http://www.sciencedirect.com/science/article/pii/S2211124724013779CP: Cancer |
| spellingShingle | Mojtaba Sadeghi Mohamed F. Salama Sam B. Chiappone Amy Huang Andrew E. Resnick Manoj Kandpal Christopher J. Clarke John D. Haley Ramana V. Davuluri Yusuf A. Hannun Biased signaling by mutant EGFR underlies dependence on PKCα in lung adenocarcinoma Cell Reports CP: Cancer |
| title | Biased signaling by mutant EGFR underlies dependence on PKCα in lung adenocarcinoma |
| title_full | Biased signaling by mutant EGFR underlies dependence on PKCα in lung adenocarcinoma |
| title_fullStr | Biased signaling by mutant EGFR underlies dependence on PKCα in lung adenocarcinoma |
| title_full_unstemmed | Biased signaling by mutant EGFR underlies dependence on PKCα in lung adenocarcinoma |
| title_short | Biased signaling by mutant EGFR underlies dependence on PKCα in lung adenocarcinoma |
| title_sort | biased signaling by mutant egfr underlies dependence on pkcα in lung adenocarcinoma |
| topic | CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124724013779 |
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