Cytokeratin19 induced by HER2ERK 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 HER2ERK 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

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30 Scopus citations

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.

Original language	English (US)
Pages (from-to)	665-676
Number of pages	12
Journal	Cell Death and Differentiation
Volume	22
Issue number	4
DOIs	https://doi.org/10.1038/cdd.2014.155
State	Published - Apr 4 2015

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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title = "Cytokeratin19 induced by HER2ERK binds and stabilizes HER2 on cell membranes",

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.",

author = "Ju, {J. H.} and S. Oh and Lee, {K. M.} and W. Yang and Nam, {K. S.} and Moon, {H. G.} and Noh, {D. Y.} and Kim, {C. G.} and G. Park and Park, {J. B.} and T. Lee and Arteaga, {C. L.} and I. Shin",

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doi = "10.1038/cdd.2014.155",

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T1 - Cytokeratin19 induced by HER2ERK binds and stabilizes HER2 on cell membranes

AU - Ju, J. H.

AU - Oh, S.

AU - Lee, K. M.

AU - Yang, W.

AU - Nam, K. S.

AU - Moon, H. G.

AU - Noh, D. Y.

AU - Kim, C. G.

AU - Park, G.

AU - Park, J. B.

AU - Lee, T.

AU - Arteaga, C. L.

AU - Shin, I.

PY - 2015/4/4

Y1 - 2015/4/4

N2 - 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.

AB - 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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Cytokeratin19 induced by HER2ERK binds and stabilizes HER2 on cell membranes

Abstract

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