title: Cytokeratin19 induced by HER2/ERK 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.
authors.affiliation: Department of Life Science, Hanyang University, Seoul, Korea.
authors.forename: J-h
authors.initials: JH
authors.lastname: Ju
authors.affiliation: Department of Life Science, Hanyang University, Seoul, Korea.
authors.forename: S
authors.initials: S
authors.lastname: Oh
authors.affiliation: Department of Life Science, Hanyang University, Seoul, Korea.
authors.forename: K-m
authors.initials: KM
authors.lastname: Lee
authors.affiliation: Department of Life Science, Hanyang University, Seoul, Korea.
authors.forename: W
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Life Science, Hanyang University, Seoul, Korea.
authors.forename: K S
authors.initials: KS
authors.lastname: Nam
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: H-G
authors.initials: HG
authors.lastname: Moon
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: D-Y
authors.initials: DY
authors.lastname: Noh
authors.affiliation: Department of Life Science, Hanyang University, Seoul, Korea.
authors.forename: C G
authors.initials: CG
authors.lastname: Kim
authors.affiliation: The Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang-si, Korea.
authors.forename: G
authors.initials: G
authors.lastname: Park
authors.affiliation: The Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang-si, Korea.
authors.forename: J B
authors.initials: JB
authors.lastname: Park
authors.affiliation: NOVA Cell Technology Inc., Pohang, Korea.
authors.forename: T
authors.initials: T
authors.lastname: Lee
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Arteaga
authors.affiliation: 1] Department of Life Science, Hanyang University, Seoul, Korea [2] Natural Science Institute, Hanyang University, Seoul, Korea.
authors.forename: I
authors.initials: I
authors.lastname: Shin
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D053539:Keratin-19 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000906:Antibodies; D048049:Extracellular Signal-Regulated MAP Kinases; D053539:Keratin-19; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases