Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, 173 Ashley Ave, BSB 358, MSC509, Charleston, SC, 29425, USA.
Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA.
Oncogene. 2020 Jan;39(5):1112-1124. doi: 10.1038/s41388-019-1046-5. Epub 2019 Oct 9.
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.
表皮生长因子受体（EGFR）在转移性乳腺癌中常过度表达，但转移性乳腺癌通常对 EGFR 靶向治疗具有抗性，且该治疗中 EGFR 抑制剂耐药的机制尚未完全阐明。激素上调的neu 相关激酶（HUNK）激酶在侵袭性乳腺癌中上调，被认为在乳腺癌转移中发挥作用。然而，目前尚无研究探讨 EGFR 和 HUNK 在乳腺癌转移中的关系。我们进行了激酶底物筛选，并鉴定出 HUNK 可使 EGFR 磷酸化。我们的研究表明，HUNK 在 T654 使 EGFR 磷酸化，增强受体稳定性和下游信号。我们发现，T654 EGFR 的磷酸化增加与上皮间质转化、迁移和侵袭以及转移增加相关。此外，我们发现 HUNK 表达与总生存期和无远处转移生存期相关。这项研究表明，HUNK 通过直接使 EGFR 在 T654 磷酸化促进转移，且这是首次显示 EGFR 该位点的磷酸化调节转移的研究。
