Centre for Cancer Biology, An Alliance of SA Pathology and the University of South Australia, Adelaide, South Australia, Australia.
The Discipline of Medicine, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia.
J Cell Biol. 2021 Feb 1;220(2). doi: 10.1083/jcb.201902073.
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.
受激活的受体酪氨酸激酶的信号转导会被受体降解所终止。表皮生长因子受体（EGFR）的降解发生在溶酶体中，需要 RAB5 在晚期内体上向 RAB7 的转换，以使其能够与溶酶体融合，但控制这种关键转换的机制还知之甚少。我们发现，酪氨酸激酶 FER 通过在 Y374 上磷酸化 PKCδ 来改变其功能，并且磷酸化的 Y374-PKCδ 可阻止 RAB5 从新生晚期内体中释放，从而抑制 EGFR 的降解，并促进内体 EGFR 循环回到细胞表面。由 PTPN14 介导的磷酸化 Y374-PKCδ 的去磷酸化作用会降低磷酸化 Y374-PKCδ 与含有 EGFR 的内体的快速结合。在三阴性乳腺癌细胞中，FER 依赖性的 PKCδ 磷酸化增强了 EGFR 信号转导，并促进了无锚定细胞生长。重要的是，在约 25%的三阴性乳腺癌患者中发现了与晚期内体成熟阻滞相关的 Y374-PKCδ 磷酸化增加，这表明该通路的失调可能导致了它们的病理。
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