Phosphorylation of PKCδ by FER tips the balance from EGFR degradation to recycling
| Autor: | Leila Belle, Gregory J. Goodall, Xiaochun Li, Nicole L. Schieber, Elizabeth V. Nguyen, Freya Gehling, Ana Lonic, Yeesim Khew-Goodall, Roger J. Daly, Robert G. Parton |
|---|---|
| Přispěvatelé: | Lonic, Ana, Gehling, Freya, Belle, Leila, Li, Xiaochun, Schieber, Nicole L, Nguyen, Elizabeth V, Goodall, Gregory J, Parton, Robert G, Daly, Roger J, Khew-Goodall, Yeesim |
| Rok vydání: | 2021 |
| Předmět: |
Time Factors
Endosome Cell Breast Neoplasms Endosomes Biology environment and public health Article Receptor tyrosine kinase 03 medical and health sciences 0302 clinical medicine trafficking Cell Line Tumor Lysosome medicine Humans cancer RNA Messenger Phosphorylation Extracellular Signal-Regulated MAP Kinases Phosphotyrosine Late endosome Cancer 030304 developmental biology 0303 health sciences Trafficking Epidermal Growth Factor Protein Stability Cell growth Ubiquitination Cell Biology Protein-Tyrosine Kinases Protein Tyrosine Phosphatases Non-Receptor Endocytosis Cell biology Enzyme Activation ErbB Receptors enzymes and coenzymes (carbohydrates) Protein Kinase C-delta Protein Transport medicine.anatomical_structure rab GTP-Binding Proteins 030220 oncology & carcinogenesis Proteolysis biology.protein Female Mitogens Tyrosine kinase |
| Zdroj: | The Journal of Cell Biology |
| ISSN: | 1540-8140 0021-9525 |
| DOI: | 10.1083/jcb.201902073 |
| Popis: | Lonic et al. show that phosphorylation of Y374-PKCδ by FER arrests the maturation of early to late endosomes by inhibiting the release of RAB5 from nascent late endosomes. This promotes EGFR recycling and sustained signaling in triple-negative breast cancer. Receptor degradation terminates signaling by activated receptor tyrosine kinases. Degradation of EGFR occurs in lysosomes and requires the switching of RAB5 for RAB7 on late endosomes to enable their fusion with the lysosome, but what controls this critical switching is poorly understood. We show that the tyrosine kinase FER alters PKCδ function by phosphorylating it on Y374, and that phospho-Y374-PKCδ prevents RAB5 release from nascent late endosomes, thereby inhibiting EGFR degradation and promoting the recycling of endosomal EGFR to the cell surface. The rapid association of phospho-Y374-PKCδ with EGFR-containing endosomes is diminished by PTPN14, which dephosphorylates phospho-Y374-PKCδ. In triple-negative breast cancer cells, the FER-dependent phosphorylation of PKCδ enhances EGFR signaling and promotes anchorage-independent cell growth. Importantly, increased Y374-PKCδ phosphorylation correlating with arrested late endosome maturation was identified in ∼25% of triple-negative breast cancer patients, suggesting that dysregulation of this pathway may contribute to their pathology. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|