CPI-17 drives oncogenic Ras signaling in human melanomas via Ezrin-Radixin-Moesin family proteins

Oncotarget. 2016 Nov 29;7(48):78242-78254. doi: 10.18632/oncotarget.12919.

Abstract

Hyperactive Ras signaling has strong oncogenic effects causing several different forms of cancer. Hyperactivity is frequently induced by mutations within Ras itself, which account for up to 30% of all human cancers. In addition, hyperactive Ras signaling can also be triggered independent of Ras by either mutation or by misexpression of various upstream regulators and immediate downstream effectors. We have previously reported that C-kinase potentiated protein phosphatase-1 inhibitor of 17 kDa (CPI-17) can drive Ras activity and promote tumorigenic transformation by inhibition of the tumor suppressor Merlin. We now describe an additional element of this oncogenic mechanism in the form of the ezrin-radixin-moesin (ERM) protein family, which exhibits opposing roles in Ras activity control. Thus, CPI-17 drives Ras activity and tumorigenesis in a two-fold way; inactivation of the tumor suppressor merlin and activation of the growth promoting ERM family. The in vivo significance of this oncogenic switch is highlighted by demonstrating CPI-17's involvement in human melanoma pathogenesis.

Keywords: CPI-17; ERM; Ras; cancer; melanoma.

MeSH terms

  • Animals
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Gene Expression Regulation, Neoplastic
  • HeLa Cells
  • Humans
  • Melanoma / enzymology*
  • Melanoma / genetics
  • Melanoma / pathology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism*
  • Myosin-Light-Chain Phosphatase / genetics
  • Myosin-Light-Chain Phosphatase / metabolism
  • NIH 3T3 Cells
  • Neurofibromin 2 / genetics
  • Neurofibromin 2 / metabolism
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism*
  • Phosphorylation
  • RNA Interference
  • Signal Transduction
  • Skin Neoplasms / enzymology*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / pathology
  • Time Factors
  • Transfection
  • ras Proteins / genetics
  • ras Proteins / metabolism*

Substances

  • Cytoskeletal Proteins
  • Membrane Proteins
  • Microfilament Proteins
  • Neurofibromin 2
  • PPP1R14A protein, human
  • ezrin
  • moesin
  • radixin
  • Phosphoprotein Phosphatases
  • Myosin-Light-Chain Phosphatase
  • PPP1R12A protein, human
  • ras Proteins