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.
Highlights
Receptor tyrosine kinases (RTKs) are critical regulators of many combinations of RTK inhibitors or broad-range RTK incellular processes, including cell proliferation, differentiation, hibitors to target multiple RTKs simultaneously can be an efmetabolism, migration, and invasion
We first verified that loss of PTPN14 by CRISPR-Cas9–mediated knockout (KO) increases steady-state cell surface levels of epidermal growth factor receptor (EGFR) in the absence of ligand (Fig. S1, a–c) and that depletion of PTPN14 did not result in a substantial overall change in total EGFR expression
Because there are clear differences in the trafficking routes of EGF-bound EGFR compared with unliganded receptor (Sorkin and Goh, 2009; Baumdick et al, 2015), we asked whether PTPN14 regulates EGF-induced trafficking of EGFR and whether this is dependent on its substrate, pY374-PKCδ (PKCδ that is phosphorylated on Y374; Belle et al, 2015)
Summary
Receptor tyrosine kinases (RTKs) are critical regulators of many combinations of RTK inhibitors or broad-range RTK incellular processes, including cell proliferation, differentiation, hibitors to target multiple RTKs simultaneously can be an efmetabolism, migration, and invasion. The unique targeted drugs has largely failed to provide durable response for changes to the kinome in response to each inhibitor, coupled cancer patients due to either intrinsic or developed resistance with the variation in response by individual tumor cells to arising from a range of mechanisms. It is be- any one inhibitor (Duncan et al, 2012), makes it difficult to coming clear that adaptive resistance to mitogen-activated pro- predict which RTKs will be up-regulated when the cancer tein kinase kinase enzyme inhibitors (MEK-Is), anaplastic becomes treatment resistant. The multiple RTKs may provide new therapeutic targets to important observation is that in both cases, the use of overcome resistance
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