Cytokeratin19 induced by HER2/ERK binds and stabilizes HER2 on cell membranes

J-h Ju; S Oh; K-m Lee; W Yang; K S Nam; H-G Moon; D-Y Noh; C G Kim; G Park; J B Park; T Lee; C L Arteaga; I Shin

doi:10.1038/cdd.2014.155

Cytokeratin19 induced by HER2/ERK binds and stabilizes HER2 on cell membranes

Cell Death Differ. 2015 Apr;22(4):665-76. doi: 10.1038/cdd.2014.155. Epub 2014 Oct 24.

Authors

J-h Ju¹, S Oh¹, K-m Lee¹, W Yang¹, K S Nam¹, H-G Moon², D-Y Noh², C G Kim¹, G Park³, J B Park³, T Lee⁴, C L Arteaga⁵, I Shin⁶

Affiliations

¹ Department of Life Science, Hanyang University, Seoul, Korea.
² Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
³ The Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang-si, Korea.
⁴ NOVA Cell Technology Inc., Pohang, Korea.
⁵ Department of Medicine, Vanderbilt University, Nashville, TN, USA.
⁶ 1] Department of Life Science, Hanyang University, Seoul, Korea [2] Natural Science Institute, Hanyang University, Seoul, Korea.

Abstract

Cytokeratin19 (KRT19) is widely used as a biomarker for the detection of disseminated tumors. Using an LC-MS/MS proteomics approach, we found that KRT19 was upregulated in HER2-overexpressing cells and tissues. KRT19 expression was induced by HER2-downstream ERK at the transcriptional level. Another HER2-downstream kinase, Akt, was found to phosphorylate KRT19 on Ser35 and induce membrane translocation of KRT19 and remodeling of KRT19 from filamentous to granulous form. KRT19 phosphorylated by Akt could bind HER2 on the plasma membrane and stabilized HER2 via inhibition of proteasome-mediated degradation of HER2. Silencing of KRT19 by shRNA resulted in increased ubiquitination and destabilization of HER2. Moreover, treatment of KRT19 antibody resulted in downregulation of HER2 and reduced cell viability. These data provide a new rationale for targeting HER2-positive breast cancers.

Publication types

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

MeSH terms

Animals
Antibodies / immunology
Antibodies / pharmacology
Antibodies / therapeutic use
Breast Neoplasms / drug therapy
Breast Neoplasms / pathology
Cell Line, Tumor
Cell Membrane / metabolism*
Cell Proliferation / drug effects
Cell Survival / drug effects
Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
Extracellular Signal-Regulated MAP Kinases / metabolism*
Female
Gene Expression Regulation
HEK293 Cells
Humans
Keratin-19 / antagonists & inhibitors
Keratin-19 / immunology
Keratin-19 / metabolism*
MAP Kinase Signaling System
MCF-7 Cells
Mice
Mice, Inbred BALB C
Mice, Nude
Mice, Transgenic
Protein Binding
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-akt / antagonists & inhibitors
Proto-Oncogene Proteins c-akt / metabolism
Receptor, ErbB-2 / chemistry
Receptor, ErbB-2 / metabolism*
Transcription, Genetic / drug effects

Substances

Antibodies
Keratin-19
Protein Kinase Inhibitors
Receptor, ErbB-2
Proto-Oncogene Proteins c-akt
Extracellular Signal-Regulated MAP Kinases