Regulation of Hippo pathway transcription factor TEAD by p38 MAPK-induced cytoplasmic translocation

Nat Cell Biol. 2017 Jul 28;19(8):996-1002. doi: 10.1038/ncb3581.

Abstract

The Hippo pathway controls organ size and tissue homeostasis, with deregulation leading to cancer. The core Hippo components in mammals are composed of the upstream serine/threonine kinases Mst1/2, MAPK4Ks and Lats1/2. Inactivation of these upstream kinases leads to dephosphorylation, stabilization, nuclear translocation and thus activation of the major functional transducers of the Hippo pathway, YAP and its paralogue TAZ. YAP/TAZ are transcription co-activators that regulate gene expression primarily through interaction with the TEA domain DNA-binding family of transcription factors (TEAD). The current paradigm for regulation of this pathway centres on phosphorylation-dependent nucleocytoplasmic shuttling of YAP/TAZ through a complex network of upstream components. However, unlike other transcription factors, such as SMAD, NF-κB, NFAT and STAT, the regulation of TEAD nucleocytoplasmic shuttling has been largely overlooked. In the present study, we show that environmental stress promotes TEAD cytoplasmic translocation via p38 MAPK in a Hippo-independent manner. Importantly, stress-induced TEAD inhibition predominates YAP-activating signals and selectively suppresses YAP-driven cancer cell growth. Our data reveal a mechanism governing TEAD nucleocytoplasmic shuttling and show that TEAD localization is a critical determinant of Hippo signalling output.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Cytoplasm / enzymology*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice, Nude
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Neoplasms / enzymology*
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Osmotic Pressure
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein Transport
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction*
  • Time Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transfection
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Muscle Proteins
  • Phosphoproteins
  • TEAD4 protein, human
  • Transcription Factors
  • WWTR1 protein, human
  • YAP1 (Yes-associated) protein, human
  • Hippo protein, human
  • Protein-Serine-Threonine Kinases
  • p38 Mitogen-Activated Protein Kinases