Identification of a co-activator that links growth factor signalling to c-Jun/AP-1 activation

Nat Cell Biol. 2010 Oct;12(10):963-72. doi: 10.1038/ncb2098. Epub 2010 Sep 19.

Abstract

The AP-1 transcription factor c-Jun is essential for cellular proliferation in many cell types, but the molecular link between growth factors and c-Jun activation has been enigmatic. In this study we identify a previously uncharacterized RING-domain-containing protein, RACO-1 (RING domain AP-1 co-activator-1), as a c-Jun co-activator that is regulated by growth factor signalling. RACO-1 interacted with c-Jun independently of amino-terminal phosphorylation, and was both necessary and sufficient for c-Jun/AP-1 activation. Growth factor-mediated stimulation of AP-1 was attributable to MEK/ERK-dependent stabilization of RACO-1 protein. Stimulation of the MEK/ERK pathway strongly promoted Lys 63-linked ubiquitylation of RACO-1, which antagonized Lys 48-linked degradative auto-ubiquitylation of the same Lys residues. RACO-1 depletion reduced cellular proliferation and decreased expression of several growth-associated AP-1 target genes, such as cdc2, cyclinD1 and hb-egf. Moreover, transgenic overexpression of RACO-1 augmented intestinal tumour formation triggered by aberrant Wnt signalling and cooperated with oncogenic Ras in colonic hyperproliferation. Thus RACO-1 is a co-activator that links c-Jun to growth factor signalling and is essential for AP-1 function in proliferation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation
  • Genes, ras / genetics
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Intestinal Neoplasms / genetics
  • Intestinal Neoplasms / metabolism
  • Intestinal Neoplasms / pathology
  • Lysine / metabolism
  • MAP Kinase Signaling System
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • NIH 3T3 Cells
  • Phosphorylation
  • Protein Binding
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Signal Transduction*
  • Transcription Factor AP-1 / metabolism*
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Ubiquitin / metabolism
  • Ubiquitination

Substances

  • Intercellular Signaling Peptides and Proteins
  • Proto-Oncogene Proteins c-jun
  • Transcription Factor AP-1
  • Transcription Factors
  • Ubiquitin
  • Mitogen-Activated Protein Kinase Kinases
  • Lysine