OTUB2 Promotes Cancer Metastasis via Hippo-Independent Activation of YAP and TAZ

Mol Cell. 2019 Jan 3;73(1):7-21.e7. doi: 10.1016/j.molcel.2018.10.030. Epub 2018 Nov 21.

Abstract

The transcriptional regulators YAP and TAZ play important roles in development, physiology, and tumorigenesis and are negatively controlled by the Hippo pathway. It is yet unknown why the YAP/ TAZ proteins are frequently activated in human malignancies in which the Hippo pathway is still active. Here, by a gain-of-function cancer metastasis screen, we discovered OTUB2 as a cancer stemness and metastasis-promoting factor that deubiquitinates and activates YAP/TAZ. We found OTUB2 to be poly-SUMOylated on lysine 233, and this SUMOylation enables it to bind YAP/TAZ. We also identified a yet-unknown SUMO-interacting motif (SIM) in YAP and TAZ required for their association with SUMOylated OTUB2. Importantly, EGF and oncogenic KRAS induce OTUB2 poly-SUMOylation and thereby activate YAP/TAZ. Our results establish OTUB2 as an essential modulator of YAP/TAZ and also reveal a novel mechanism via which YAP/TAZ activity is induced by oncogenic KRAS.

Keywords: OTUB2; SUMOylation; YAP/TAZ; deubiquitination; metastasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Movement* / drug effects
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / agonists
  • ErbB Receptors / metabolism
  • Female
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lysine
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mutation
  • Neoplasm Metastasis
  • Neoplastic Stem Cells / enzymology*
  • Neoplastic Stem Cells / pathology
  • Phenotype
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Proteolysis
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Signal Transduction
  • Sumoylation
  • Thiolester Hydrolases / genetics
  • Thiolester Hydrolases / metabolism*
  • Time Factors
  • Trans-Activators
  • Transcription Factors
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Intracellular Signaling Peptides and Proteins
  • KRAS protein, human
  • Phosphoproteins
  • Trans-Activators
  • Transcription Factors
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • WWTR1 protein, human
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • Epidermal Growth Factor
  • EGFR protein, human
  • ErbB Receptors
  • OTUB2 protein, human
  • Thiolester Hydrolases
  • Proteasome Endopeptidase Complex
  • Proto-Oncogene Proteins p21(ras)
  • Lysine