Phosphorylation of the Tumor Suppressor CYLD by the Breast Cancer Oncogene IKKε Promotes Cell Transformation Academic Article uri icon

Overview

MeSH Major

  • Breast Neoplasms
  • Cell Transformation, Neoplastic
  • I-kappa B Kinase
  • Tumor Suppressor Proteins

abstract

  • The noncanonical IKK family member IKKepsilon is essential for regulating antiviral signaling pathways and is a recently discovered breast cancer oncoprotein. Although several IKKepsilon targets have been described, direct IKKepsilon substrates necessary for regulating cell transformation have not been identified. Here, we performed a screen for putative IKKepsilon substrates using an unbiased proteomic and bioinformatic approach. Using a positional scanning peptide library assay, we determined the optimal phosphorylation motif for IKKepsilon and used bioinformatic approaches to predict IKKepsilon substrates. Of these potential substrates, serine 418 of the tumor suppressor CYLD was identified as a likely site of IKKepsilon phosphorylation. We confirmed that CYLD is directly phosphorylated by IKKepsilon and that IKKepsilon phosphorylates serine 418 in vivo. Phosphorylation of CYLD at serine 418 decreases its deubiquitinase activity and is necessary for IKKepsilon-driven transformation. Together, these observations define IKKepsilon and CYLD as an oncogene-tumor suppressor network that participates in tumorigenesis.

publication date

  • May 14, 2009

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2746958

Digital Object Identifier (DOI)

  • 10.1016/j.molcel.2009.04.031

PubMed ID

  • 19481526

Additional Document Info

start page

  • 461

end page

  • 72

volume

  • 34

number

  • 4