Phosphoproteomic analysis identifies the tumor suppressor PDCD4 as a RSK substrate negatively regulated by 14-3-3 Academic Article uri icon


MeSH Major

  • Apoptosis Regulatory Proteins
  • Phosphoproteins
  • Proteomics
  • RNA-Binding Proteins
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Tumor Suppressor Proteins


  • The Ras/MAPK signaling cascade regulates various biological functions, including cell growth and proliferation. As such, this pathway is frequently deregulated in several types of cancer, including most cases of melanoma. RSK (p90 ribosomal S6 kinase) is a MAPK-activated protein kinase required for melanoma growth and proliferation, but relatively little is known about its exact function and the nature of its substrates. Herein, we used a quantitative phosphoproteomics approach to define the signaling networks regulated by RSK in melanoma. To more accurately predict direct phosphorylation substrates, we defined the RSK consensus phosphorylation motif and found significant overlap with the binding consensus of 14-3-3 proteins. We thus characterized the phospho-dependent 14-3-3 interactome in melanoma cells and found that a large proportion of 14-3-3 binding proteins are also potential RSK substrates. Our results show that RSK phosphorylates the tumor suppressor PDCD4 (programmed cell death protein 4) on two serine residues (Ser76 and Ser457) that regulate its subcellular localization and interaction with 14-3-3 proteins. We found that 14-3-3 binding promotes PDCD4 degradation, suggesting an important role for RSK in the inactivation of PDCD4 in melanoma. In addition to this tumor suppressor, our results suggest the involvement of RSK in a vast array of unexplored biological functions with relevance in oncogenesis.

publication date

  • July 22, 2014



  • Academic Article



  • eng

PubMed Central ID

  • PMC4115529

Digital Object Identifier (DOI)

  • 10.1073/pnas.1405601111

PubMed ID

  • 25002506

Additional Document Info

start page

  • E2918

end page

  • 27


  • 111


  • 29