CBL mutations drive PI3K/AKT signaling via increased interaction with LYN and PIK3R1
Autor: | Christina R. Hartigan, Benjamin L. Ebert, Caroline Stanclift, Namrata D. Udeshi, Monica Schenone, Amanuel Bizuayehu, Veronica Kovalcik, Tanya Svinkina, Alexis Vedder, Marie McConkey, Eric Padron, Sebastian Koochaki, Roger Belizaire, Steven A. Carr, Lei Sun |
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Rok vydání: | 2021 |
Předmět: |
Immunology
medicine.disease_cause environment and public health Biochemistry Phosphatidylinositol 3-Kinases LYN PIK3R1 hemic and lymphatic diseases medicine Humans Protein Interaction Maps Proto-Oncogene Proteins c-cbl Protein kinase B PI3K/AKT/mTOR pathway Mutation Myeloid Neoplasia biology Chemistry fungi Cell Biology Hematology Ubiquitin ligase Class Ia Phosphatidylinositol 3-Kinase enzymes and coenzymes (carbohydrates) src-Family Kinases Hematologic Neoplasms biology.protein Cancer research Phosphorylation biological phenomena cell phenomena and immunity Proto-Oncogene Proteins c-akt Tyrosine kinase Signal Transduction |
Zdroj: | Blood |
ISSN: | 1528-0020 0006-4971 |
Popis: | Casitas B-lineage lymphoma (CBL) encodes an E3 ubiquitin ligase and signaling adaptor that regulates receptor and nonreceptor tyrosine kinases. Recurrent CBL mutations occur in myeloid neoplasms, including 10% to 20% of chronic myelomonocytic leukemia (CMML) cases, and selectively disrupt the protein’s E3 ubiquitin ligase activity. CBL mutations have been associated with poor prognosis, but the oncogenic mechanisms and therapeutic implications of CBL mutations remain incompletely understood. We combined functional assays and global mass spectrometry to define the phosphoproteome, CBL interactome, and mechanism of signaling activation in a panel of cell lines expressing an allelic series of CBL mutations. Our analyses revealed that increased LYN activation and interaction with mutant CBL are key drivers of enhanced CBL phosphorylation, phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) recruitment, and downstream phosphatidylinositol 3-kinase (PI3K)/AKT signaling in CBL-mutant cells. Signaling adaptor domains of CBL, including the tyrosine kinase–binding domain, proline-rich region, and C-terminal phosphotyrosine sites, were all required for the oncogenic function of CBL mutants. Genetic ablation or dasatinib-mediated inhibition of LYN reduced CBL phosphorylation, CBL-PIK3R1 interaction, and PI3K/AKT signaling. Furthermore, we demonstrated in vitro and in vivo antiproliferative efficacy of dasatinib in CBL-mutant cell lines and primary CMML. Overall, these mechanistic insights into the molecular function of CBL mutations provide rationale to explore the therapeutic potential of LYN inhibition in CBL-mutant myeloid malignancies. |
Databáze: | OpenAIRE |
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