Interaction between ERK and GSK3β mediates basic fibroblast growth factor-induced apoptosis in SK-N-MC neuroblastoma cells

Cuiling Ma, Kimberly A. Bower, Gang Chen, Xianglin Shi, Zun Ji Ke, Jia Luo

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


The Ewing's sarcoma family of tumors (ESFT) includes Ewing's sarcoma (ES), Askin's tumor of the chest wall, and peripheral primitive neuroectodermal tumor. Basic fibroblast growth factor (FGF2) suppresses the growth of ESFT cells and causes their apoptosis. The underlying mechanism is unclear. Using a human peripheral primitive neuroectodermal tumor cell line, SK-N-MC, we demonstrated FGF2 stimulated phosphorylation of ERK1 and ERK2 (pERK1/2) and GSK3β (pGSK3β(Tyr-216)), all of which were primarily retained in the cytoplasm. FGF2 promoted the association between ERK and pGSK3β(Tyr-216). Inhibitors for GSK3β(TDZD and LiCl) and ERK (PD98059) protected cells from FGF2-induced apoptosis. On the other hand, inhibitors of GSK3β, but not PD98059 decreased ERK/pGSK3β(Tyr-216) association and caused a nuclear translocation of pERK1/2. Similarly, expression of a kinase-deficient (K85R) GSK3β or GSK3β-small interfering RNA inhibited FGF2-regulated ERK/pGSK3β(Tyr-216) association and translocated pERK to the nucleus. Both K85R GSK3β and small interfering RNA offered protection against FGF2-induced cell death. In contrast, overexpression of wild-type GSK3β sensitized cells to FGF2 cytotoxicity. Hydrogen peroxide and ethanol enhanced FGF2-stimulated pGSK3β(Tyr-216), ERK/pGSK3β(Tyr-216) association, and cytoplasmic retention of pERK1/2. As a result, they potentiated FGF2-induced cell death. Taken together, our results suggested that FGF2-induced accumulation of pERK1/2 in the cytoplasm is toxic for SK-N-MC cells. The formation of an ERK·GSK3β complex retained pERK1/2 in the cytoplasm. In contrast, disruption of the ERK·GSK3β complex resulted in nuclear translocation of pERK1/2 and offered protection.

Original languageEnglish
Pages (from-to)9248-9256
Number of pages9
JournalJournal of Biological Chemistry
Issue number14
StatePublished - Apr 4 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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