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.
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Abbreviations
- KRTs:
-
cytokeratins
- KRT19:
-
cytokeratin19
- ERK:
-
extracellular signal-regulated protein kinase
- WT:
-
wild type
- TG:
-
transgenic
- HA-Akt1-CA:
-
constitutively active Akt1
- HA-Akt1-KD:
-
kinase-dead Akt1
- HER2-FL-myc:
-
full-length HER2
- HER2-ICD-myc:
-
intracellular HER2
- HER2-ECD-myc:
-
extracellular HER2
- CHX:
-
cycloheximide
- VEGF:
-
vascular endothelial growth factor
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Acknowledgements
This work was supported by NRF grant (2013-059143) from the Korea Research Foundation and the Converging Research Center Program funded by Ministry of Science, ICT & Future Planning (Project No. 2014048814). We thank Dr. Omary (Stanford University), Dr. Rustgi (Univ of Pennsylvania) and Dr. Su-Jae Lee for the plasmid constructs.
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Ju, Jh., Oh, S., Lee, Km. et al. Cytokeratin19 induced by HER2/ERK binds and stabilizes HER2 on cell membranes. Cell Death Differ 22, 665–676 (2015). https://doi.org/10.1038/cdd.2014.155
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DOI: https://doi.org/10.1038/cdd.2014.155
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