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Published on: May 26, 2017
Phosphorylation of PKCδ by FER tips the balance from EGFR degradation to recycling
Ana Lonic1,2, Freya Gehling1, Leila Belle1
1Centre for Cancer Biology, An Alliance of SA Pathology and the University of South Australia, Adelaide, South Australia, Australia.
Abstract:
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.
Insights
The FER kinase phosphorylates PKCδ, halting EGFR degradation and promoting receptor recycling. This pathway is dysregulated in triple-negative breast cancer, impacting cell growth.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Receptor tyrosine kinase (RTK) signaling termination is crucial for cellular homeostasis.
- Epidermal Growth Factor Receptor (EGFR) degradation occurs via lysosomes, requiring endosome maturation.
- The molecular mechanisms controlling the switch from early to late endosomes for EGFR degradation are not fully understood.
Purpose of the Study:
- To elucidate the role of tyrosine kinase FER and PKCδ in regulating EGFR degradation.
- To investigate the impact of FER-mediated PKCδ phosphorylation on endosomal trafficking.
- To explore the relevance of this pathway in triple-negative breast cancer (TNBC).
Main Methods:
- Phosphorylation site mapping of PKCδ.
- Endosomal trafficking assays using fluorescently tagged proteins.
- Western blotting and immunoprecipitation to detect protein interactions.
- Analysis of patient tumor samples.
Main Results:
- Tyrosine kinase FER phosphorylates PKCδ at Y374, stabilizing phospho-Y374-PKCδ on endosomes.
- Phospho-Y374-PKCδ inhibits RAB5 release, preventing late endosome maturation and lysosomal fusion.
- This leads to reduced EGFR degradation and increased EGFR recycling to the cell surface.
- PTPN14 dephosphorylates phospho-Y374-PKCδ, facilitating endosome maturation.
- FER-dependent PKCδ phosphorylation promotes EGFR signaling and anchorage-independent growth in TNBC cells.
- Elevated phospho-Y374-PKCδ and impaired late endosome maturation are observed in a subset of TNBC patients.
Conclusions:
- FER-mediated phosphorylation of PKCδ is a critical regulator of EGFR degradation.
- Dysregulation of the FER-PKCδ-EGFR axis contributes to TNBC progression.
- Targeting this pathway may offer therapeutic strategies for TNBC.
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