Block one, unleash a hundred. Mechanisms of DAB2IP inactivation in cancer

Cell Death Differ. 2017 Jan;24(1):15-25. doi: 10.1038/cdd.2016.134. Epub 2016 Nov 18.


One of the most defining features of cancer is aberrant cell communication; therefore, a molecular understanding of the intricate network established among tumor cells and their microenvironment could significantly improve comprehension and clinical management of cancer. The tumor suppressor DAB2IP (Disabled homolog 2 interacting protein), also known as AIP1 (ASK1 interacting protein), has an important role in this context, as it modulates signal transduction by multiple inflammatory cytokines and growth factors. DAB2IP is a Ras-GAP, and negatively controls Ras-dependent mitogenic signals. In addition, acting as a signaling adaptor, DAB2IP modulates other key oncogenic pathways, including TNFα/NF-κB, WNT/β-catenin, PI3K/AKT, and androgen receptors. Therefore, DAB2IP inactivation can provide a selective advantage to tumors initiated by a variety of driver mutations. In line with this role, DAB2IP expression is frequently impaired by methylation in cancer. Interestingly, recent studies reveal that tumor cells can employ other sophisticated mechanisms to disable DAB2IP at the post-transcriptional level. We review the mechanisms and consequences of DAB2IP inactivation in cancer, with the purpose to support and improve research aimed to counteract such mechanisms. We suggest that DAB2IP reactivation in cancer cells could be a strategy to coordinately dampen multiple oncogenic pathways, potentially limiting progression of a wide spectrum of tumors.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Drug Resistance, Neoplasm
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Kinase Kinase 5 / metabolism
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • Neoplastic Stem Cells / metabolism
  • Signal Transduction
  • Ubiquitin / metabolism
  • ras GTPase-Activating Proteins / chemistry
  • ras GTPase-Activating Proteins / genetics
  • ras GTPase-Activating Proteins / metabolism*


  • DAB2IP protein, human
  • Ubiquitin
  • ras GTPase-Activating Proteins
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 5