Regulation of Hippo signaling by EGFR-MAPK signaling through Ajuba family proteins

Dev Cell. 2013 Mar 11;24(5):459-71. doi: 10.1016/j.devcel.2013.01.020.

Abstract

EGFR and Hippo signaling pathways both control growth and, when dysregulated, contribute to tumorigenesis. We find that EGFR activates the Hippo pathway transcription factor Yorkie and demonstrate that Yorkie is required for the influence of EGFR on cell proliferation in Drosophila. EGFR regulates Yorkie through the influence of its Ras-MAPK branch on the Ajuba LIM protein Jub. Jub is epistatic to EGFR and Ras for Yorkie regulation, Jub is subject to MAPK-dependent phosphorylation, and EGFR-Ras-MAPK signaling enhances Jub binding to the Yorkie kinase Warts and the adaptor protein Salvador. An EGFR-Hippo pathway link is conserved in mammals, as activation of EGFR or RAS activates the Yorkie homolog YAP, and EGFR-RAS-MAPK signaling promotes phosphorylation of the Ajuba family protein WTIP and also enhances WTIP binding to the Warts and Salvador homologs LATS and WW45. Our observations implicate the Hippo pathway in EGFR-mediated tumorigenesis and identify a molecular link between these pathways.

Publication types

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

MeSH terms

  • Animals
  • Blotting, Western
  • Drosophila Proteins / antagonists & inhibitors
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / chemistry
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism*
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Immunoprecipitation
  • LIM Domain Proteins / genetics
  • LIM Domain Proteins / metabolism*
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptors, Invertebrate Peptide / antagonists & inhibitors
  • Receptors, Invertebrate Peptide / genetics
  • Receptors, Invertebrate Peptide / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction*
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • ras Proteins / genetics
  • ras Proteins / metabolism*

Substances

  • Drosophila Proteins
  • LIM Domain Proteins
  • Nuclear Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptors, Invertebrate Peptide
  • Trans-Activators
  • Yki protein, Drosophila
  • jub protein, Drosophila
  • ras protein, Dictyostelium
  • Egfr protein, Drosophila
  • ErbB Receptors
  • ras Proteins