Glycogen synthase kinase-3 is a negative regulator of extracellular signal-regulated kinase

Q. Wang, Y. Zhou, X. Wang, B. M. Evers

Research output: Contribution to journalArticlepeer-review

120 Scopus citations


Glycogen-synthase kinase-3 (GSK-3) and extracellular signal-regulated kinase (ERK) are critical downstream signaling proteins for the PI3-kinase/Akt and Ras/Raf/MEK-1 pathway, respectively, and regulate diverse cellular processes including embryonic development, cell differentiation and apoptosis. Here, we show that inhibition of GSK-3 using GSK-3 inhibitors or RNA interference (RNAi) significantly induced the phosphorylation of ERK1/2 in human colon cancer cell lines HT29 and Caco-2. Pretreatment with the PKCδ-selective inhibitor rottlerin or transfection with PKCδ siRNA attenuated the phosphorylation of ERK1/2 induced by the GSK-3 inhibitor SB-216763 and, furthermore, treatment with SB-216763 or transfection with GSK-3α and GSK-3β siRNA increased PKCδ activity, thus identifying a role for PKCδ in the induction of ERK1/2 phosphorylation by GSK-3 inhibition. Treatment with SB-216763 increased expression of cyclooxygenase-2 (COX-2) and IL-8, which are downstream targets of ERK1/2 activation; this induction was abolished by MEK/ERK inhibition, suggesting GSK-3 inhibition induced COX-2 and IL-8 through ERK1/2 activation. The transcriptional induction of COX-2 and IL-8 by GSK-3 inhibition was further demonstrated by the increased COX-2 and IL-8 promoter activity after SB-216763 treatment or transfection with GSK-3α or GSK-3β siRNA. Importantly, our findings identify GSK-3, acting through PKCδ, as a negative regulator of ERK1/2, thus revealing a novel crosstalk mechanism between these critical signaling pathways.

Original languageEnglish
Pages (from-to)43-50
Number of pages8
Issue number1
StatePublished - Jan 5 2006

Bibliographical note

Funding Information:
We thank Eileen Figueroa and Karen Martin for manuscript preparation. This work was supported by Grants RO1 DK48498, R37 AG10885 and PO1 DK35608 from the National Institutes of Health.


  • Colon cancer cells
  • ERK
  • GSK-3
  • MAPK
  • PKCδ
  • siRNA

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research


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