ArticleScience signaling2018
Truncation- and motif-based pan-cancer analysis reveals tumor-suppressing kinases.
Article in Science signaling, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 15 citations in OpenAlex.
- Frequent EPHA2 receptor mutations in cholangiocarcinoma disrupt receptor forward signaling supporting a tumor suppressor role.Biochimica et biophysica acta. Molecular cell research · 2026Article
- Comprehensively Testing the Function of Missense Variation in thebioRxiv : the preprint server for biology · 2025Article
- A missense variant effect map for the human tumor-suppressor protein CHK2.American journal of human genetics · 2024Article
- HER2-driven breast cancer suppression by the JNK signaling pathway.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Changes in antioxidant status and DNA repair capacity are corroborated with molecular alterations in malignant thyroid tissue of patients with papillary thyroid cancer.Frontiers in molecular biosciences · 2023Article
- Protein kinase C: release from quarantine by mTORC2.Trends in biochemical sciences · 2022Review
- Characterization of genomic alterations and neoantigens and analysis of immune infiltration identified therapeutic and prognostic biomarkers in adenocarcinoma at the gastroesophageal junction.Frontiers in oncology · 2022Article
- A Signature of NFrontiers in immunology · 2022Article
- A tumor-associated splice-isoform ofProceedings of the National Academy of Sciences of the United States of America · 2020Article
- The autoinhibited state of MKK4: Phosphorylation, putative dimerization and R134W mutant studied by molecular dynamics simulations.Computational and structural biotechnology journal · 2020Article
- Orange is the new black: Kinases are the new master regulators of tumor suppression.IUBMB life · 2019Review
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Authors and funding
12 authors at 5 institutions in 3 countries.
Funding
Abstract
A major challenge in cancer genomics is identifying "driver" mutations from the many neutral "passenger" mutations within a given tumor. To identify driver mutations that would otherwise be lost within mutational noise, we filtered genomic data by motifs that are critical for kinase activity. In the first step of our screen, we used data from the Cancer Cell Line Encyclopedia and The Cancer Genome Atlas to identify kinases with truncation mutations occurring within or before the kinase domain. The top 30 tumor-suppressing kinases were aligned, and hotspots for loss-of-function (LOF) mutations were identified on the basis of amino acid conservation and mutational frequency. The functional consequences of new LOF mutations were biochemically validated, and the top 15 hotspot LOF residues were used in a pan-cancer analysis to define the tumor-suppressing kinome. A ranked list revealed MAP2K7, an essential mediator of the c-Jun N-terminal kinase (JNK) pathway, as a candidate tumor suppressor in gastric cancer, despite its mutational frequency falling within the mutational noise for this cancer type. The majority of mutations in MAP2K7 abolished its catalytic activity, and reactivation of the JNK pathway in gastric cancer cells harboring LOF mutations in MAP2K7 or the downstream kinase JNK suppressed clonogenicity and growth in soft agar, demonstrating the functional relevance of inactivating the JNK pathway in gastric cancer. Together, our data highlight a broadly applicable strategy to identify functional cancer driver mutations and define the JNK pathway as tumor-suppressive in gastric cancer.
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