Ect2 links the PKC-Par6α complex to Rac1 activation and cellular transformation

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

Protein kinase C (PKC) promotes non-small cell lung cancer (NSCLC) by binding to Par6α and activating a Rac1-Pak-Mek1,2-Erk1,2 signaling cascade. The mechanism by which the PKC-Par6α complex regulates Rac1 is unknown. Here we show that epithelial cell transforming sequence 2 (Ect2), a guanine nucleotide exchange factor for Rho family GTPases, is coordinately amplified and overexpressed with PKC in NSCLC tumors. RNA interference-mediated knockdown of Ect2 inhibits Rac1 activity and blocks transformed growth, invasion and tumorigenicity of NSCLC cells. Expression of constitutively active Rac1 (RacV12) restores transformation to Ect2-deficient cells. Interestingly, the role of Ect2 in transformation is distinct from its well-established role in cytokinesis. In NSCLC cells, Ect2 is mislocalized to the cytoplasm where it binds the PKC-Par6α complex. RNA interference-mediated knockdown of either PKC or Par6α causes Ect2 to redistribute to the nucleus, indicating that the PKC-Par6α complex regulates the cytoplasmic localization of Ect2. Our data indicate that Ect2 and PKC are genetically and functionally linked in NSCLC, acting to coordinately drive tumor cell proliferation and invasion through formation of an oncogenic PKC-Par6α-Ect2 complex.

Original languageEnglish (US)
Pages (from-to)3597-3607
Number of pages11
JournalOncogene
Volume28
Issue number41
DOIs
StatePublished - Oct 15 2009

Fingerprint

Protein Kinase C
Epithelial Cells
Non-Small Cell Lung Carcinoma
RNA Interference
Guanine Nucleotide Exchange Factors
link protein
rho GTP-Binding Proteins
Cytokinesis
Neoplasms
Cytoplasm
Cell Proliferation
Growth

Keywords

  • Anchorage-independent growth
  • Cytokinesis
  • Gene amplification
  • Invasion
  • Mek-Erk signaling
  • Rac1

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Biology

Cite this

Ect2 links the PKC-Par6α complex to Rac1 activation and cellular transformation. / Justilien, Verline; Fields, Alan P.

In: Oncogene, Vol. 28, No. 41, 15.10.2009, p. 3597-3607.

Research output: Contribution to journalArticle

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