PEA-15 potentiates H-Ras-mediated epithelial cell transformation through phospholipase D

Oncogene. 2012 Jul 26;31(30):3547-60. doi: 10.1038/onc.2011.514. Epub 2011 Nov 21.

Abstract

The small GTPase H-Ras is a proto-oncogene that activates a variety of different pathways including the extracellular-signal-regulated kinase (ERK)/mitogen-activated protein kinase pathway. H-Ras is mutated in many human malignancies, and these mutations cause the protein to be constitutively active. Phosphoprotein enriched in astrocytes, 15 kDa (PEA-15) blocks ERK-dependent gene transcription and inhibits proliferation by sequestering ERK in the cytoplasm. We therefore investigated whether PEA-15 influences H-Ras-mediated transformation. We found that PEA-15 does not block H-Ras-activated proliferation when H-Ras is constitutively active. We show instead that in H-Ras-transformed mouse kidney epithelial cells, co-expression of PEA-15 resulted in enhanced soft agar colony growth and increased tumor growth in vivo. Overexpression of both H-Ras and PEA-15 resulted in accelerated G1/S cell cycle transition and increased activation of the ERK signaling pathway. PEA-15 mediated these effects through activation of its binding partner phospholipase D1 (PLD1). Inhibition of PLD1 or interference with PEA-15/PLD1 binding blocked PEA-15's ability to increase ERK activation. Our findings reveal a novel mechanism by which PEA-15 positively regulates Ras/ERK signaling and increases the proliferation of H-Ras-transformed epithelial cells through enhanced PLD1 expression and activation. Thus, our work provides a surprising mechanism by which PEA-15 augments H-Ras-driven transformation. These data reveal that PEA-15 not only suppresses ERK signaling and tumorigenesis but also alternatively enhances tumorigenesis in the context of active Ras.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins
  • Cell Line
  • Cell Proliferation
  • Cell Transformation, Neoplastic / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Kidney / metabolism
  • MAP Kinase Signaling System / physiology
  • Mice
  • Mice, Nude
  • Phospholipase D / antagonists & inhibitors
  • Phospholipase D / metabolism*
  • Phosphoproteins / metabolism*
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins p21(ras) / metabolism*

Substances

  • Apoptosis Regulatory Proteins
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • MAS1 protein, human
  • PEA15 protein, human
  • Phosphoproteins
  • Proto-Oncogene Mas
  • Phospholipase D
  • phospholipase D1
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)