Phosphorylation of PKCδ by FER tips the balance from EGFR degradation to recycling

Ana Lonic; Freya Gehling; Leila Belle; Xiaochun Li; Nicole L Schieber; Elizabeth V Nguyen; Gregory J Goodall; Robert G Parton; Roger J Daly; Yeesim Khew-Goodall

doi:10.1083/jcb.201902073

Phosphorylation of PKCδ by FER tips the balance from EGFR degradation to recycling

J Cell Biol. 2021 Feb 1;220(2):e201902073. doi: 10.1083/jcb.201902073.

Authors

Ana Lonic^{1

2}, Freya Gehling¹, Leila Belle¹, Xiaochun Li¹, Nicole L Schieber³, Elizabeth V Nguyen⁴, Gregory J Goodall^{1

2

5}, Robert G Parton^{3

6}, Roger J Daly⁴, Yeesim Khew-Goodall^{1

2

7}

Affiliations

¹ Centre for Cancer Biology, An Alliance of SA Pathology and the University of South Australia, Adelaide, South Australia, Australia.
² The Discipline of Medicine, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia.
³ Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland, Australia.
⁴ Cancer Program, Biomedicine Discovery Institute, and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
⁵ School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia.
⁶ Centre for Microscopy and Microanalysis, The University of Queensland, St. Lucia, Queensland, Australia.
⁷ Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Cell Line, Tumor
Endocytosis* / drug effects
Endosomes / drug effects
Endosomes / metabolism
Enzyme Activation / drug effects
Epidermal Growth Factor / pharmacology
ErbB Receptors / genetics
ErbB Receptors / metabolism
Extracellular Signal-Regulated MAP Kinases / metabolism
Female
Humans
Mitogens / pharmacology
Phosphorylation / drug effects
Phosphotyrosine / metabolism
Protein Kinase C-delta / metabolism*
Protein Stability / drug effects
Protein Transport / drug effects
Protein Tyrosine Phosphatases, Non-Receptor / deficiency
Protein Tyrosine Phosphatases, Non-Receptor / metabolism
Protein-Tyrosine Kinases / metabolism*
Proteolysis* / drug effects
RNA, Messenger / genetics
RNA, Messenger / metabolism
Time Factors
Ubiquitination / drug effects
rab GTP-Binding Proteins / metabolism

Substances

Mitogens
RNA, Messenger
proto-oncogene protein c-fes-fps
Phosphotyrosine
Epidermal Growth Factor
EGFR protein, human
ErbB Receptors
Protein-Tyrosine Kinases
Protein Kinase C-delta
Extracellular Signal-Regulated MAP Kinases
PTPN14 protein, human
Protein Tyrosine Phosphatases, Non-Receptor
rab GTP-Binding Proteins