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NG2, a novel proapoptotic receptor, opposes integrin alpha4 to mediate anoikis through PKCalpha-dependent suppression

N E Joo1, T Watanabe, C Chen

  • 1Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI 48109-1078, USA.

Cell Death and Differentiation
|February 23, 2008
PubMed

Insights

Altered fibronectin matrix induces fibroblast apoptosis (anoikis) by upregulating the NG2 receptor and downregulating integrin alpha4. Suppressing NG2 or increasing alpha4 prevents anoikis, revealing novel cell-matrix interaction pathways.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Disruption of cell-matrix interactions triggers anoikis, a form of apoptosis.
  • Altered fibronectin matrices induce fibroblast anoikis via reduced focal adhesion kinase (FAK) phosphorylation.
  • The specific receptors mediating this process were previously unknown.

Purpose of the Study:

  • To identify the receptors involved in fibronectin-induced anoikis.
  • To elucidate the signaling pathways regulating FAK phosphorylation in response to matrix changes.
  • To investigate the opposing roles of NG2 and integrin alpha4 in anoikis.

Main Methods:

  • Primary human fibroblasts were cultured on altered fibronectin matrices.
  • Gene expression of NG2 and integrin alpha4 was modulated using siRNA and cDNA.
  • Phosphorylation levels of FAK and expression of PKCalpha were assessed.
  • Cell viability assays were performed to determine anoikis rates.

Main Results:

  • An altered fibronectin matrix upregulated NG2 and downregulated integrin alpha4, inducing anoikis.
  • Suppression of NG2 or overexpression of integrin alpha4 rescued fibroblasts from anoikis.
  • NG2 overexpression alone induced apoptosis and enhanced anoikis by reducing FAK phosphorylation.
  • Integrin alpha4 enhanced FAK phosphorylation independently of PKCalpha, while NG2 and altered matrix suppressed PKCalpha.

Conclusions:

  • Nerve/glial antigen 2 (NG2) acts as a novel proapoptotic receptor in fibroblasts.
  • NG2 and integrin alpha4 exert opposing effects on anoikis.
  • NG2 and integrin alpha4 differentially regulate FAK phosphorylation through PKCalpha-dependent and -independent pathways, respectively.

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