Tankyrase Inhibitors Target YAP by Stabilizing Angiomotin Family Proteins

Cell Rep. 2015 Oct 20;13(3):524-532. doi: 10.1016/j.celrep.2015.09.014. Epub 2015 Oct 8.

Abstract

As the key effector in the Hippo pathway, YAP was identified as an oncoprotein whose expression is elevated in various human cancers. However, the development of potentially therapeutic compounds targeting YAP has been slow and limited. Here, we find that tankyrase inhibitors suppress YAP activity. This effect is mediated by anigomotin (AMOT) family proteins. Tankyrases associate with AMOT family proteins and promote their degradation through E3 ligase RNF146. By antagonizing tankyrase activity, tankyrase inhibitors stabilize AMOT family proteins, thereby suppressing YAP oncogenic functions. Together, our studies not only demonstrate the tankyrase-RNF146-AMOT axis as an upstream pathway regulating YAP but also reveal a therapeutic opportunity in targeting YAP for cancer treatment.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Enzyme Inhibitors / pharmacology*
  • HEK293 Cells
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • MCF-7 Cells
  • Membrane Proteins / metabolism*
  • Phosphoproteins / metabolism*
  • Protein Binding
  • Protein Stability
  • Proteolysis*
  • Sulfones / pharmacology
  • Tankyrases / antagonists & inhibitors*
  • Tankyrases / metabolism
  • Transcription Factors
  • Triazoles / pharmacology
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • AMOT protein, human
  • Adaptor Proteins, Signal Transducing
  • Enzyme Inhibitors
  • G007-LK
  • Heterocyclic Compounds, 3-Ring
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Phosphoproteins
  • Sulfones
  • Transcription Factors
  • Triazoles
  • XAV939
  • YAP1 (Yes-associated) protein, human
  • RNF146 protein, human
  • Ubiquitin-Protein Ligases
  • Tankyrases