HUNK phosphorylates EGFR to regulate breast cancer metastasis

Epidermal growth factor receptor (EGFR) is commonly over-expressed in metastatic breast cancer yet metastatic breast cancer is generally resistant to anti-EGFR therapies, and the mechanism for resistance to EGFR inhibitors in this setting is not fully understood. Hormonally up-regulated neu-associat...

Full description

Saved in:
Bibliographic Details
Published in:Oncogene 2020-01, Vol.39 (5), p.1112-1124
Main Authors: Williams, Carly B., Phelps-Polirer, Kendall, Dingle, Ivan P., Williams, Christina J., Rhett, Matthew J., Eblen, Scott T., Armeson, Kent, Hill, Elizabeth G., Yeh, Elizabeth S.
Format: Article
Language:English
Subjects:
13/106
13/95
631/67/1347
631/80/304
64/60
96/109
Animals
Apoptosis
B cells
Breast cancer
Breast Neoplasms - pathology
Cancer
Cell Biology
Cell Line, Tumor
Cell Movement
Cell Transformation, Neoplastic
Epidermal growth factor
Epidermal growth factor receptors
Epithelial-Mesenchymal Transition
ErbB Receptors - metabolism
Female
Human Genetics
Humans
Internal Medicine
Medicine
Medicine & Public Health
Mesenchyme
Metastases
Metastasis
Mice
Neoplasm Invasiveness
Neoplasm Metastasis
Neu-associated kinase
Oncology
Oncology, Experimental
Phosphorylation
Protein Serine-Threonine Kinases - metabolism
Signal Transduction
Survival
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Epidermal growth factor receptor (EGFR) is commonly over-expressed in metastatic breast cancer yet metastatic breast cancer is generally resistant to anti-EGFR therapies, and the mechanism for resistance to EGFR inhibitors in this setting is not fully understood. Hormonally up-regulated neu-associated kinase (HUNK) kinase is up-regulated in aggressive breast cancers and is thought to play a role in breast cancer metastasis. However, no studies have been conducted to examine a relationship between EGFR and HUNK in breast cancer metastasis. We performed a kinase substrate screen and identified that EGFR is phosphorylated by HUNK. Our studies show that HUNK phosphorylates EGFR at T654, enhancing receptor stability and downstream signaling. We found that increased phosphorylation of T654 EGFR correlates with increased epithelial to mesenchymal, migration and invasion, and metastasis. In addition, we found that HUNK expression correlates with overall survival and distant metastasis free survival. This study shows that HUNK directly phosphorylates EGFR at T654 to promote metastasis and is the first study to show that the phosphorylation of this site in EGFR regulates metastasis.
ISSN:0950-9232
1476-5594
DOI:10.1038/s41388-019-1046-5