EGF receptor is involved in WNT3a-mediated proliferation and motility of NIH3T3 cells via ERK pathway activation

Cell Signal. 2007 Jul;19(7):1554-64. doi: 10.1016/j.cellsig.2007.02.003. Epub 2007 Feb 20.


WNT3a stimulates proliferation of NIH3T3 cells via activation of the extracellular signal-regulated kinase (ERK) pathway. The RAF-1-->MEK-->ERK cascade was immediately increased by WNT3a treatment, however, the upstream event triggering ERK pathway activation by WNT3a is not clear. WNT3a activated RAS and WNT3a-induced ERK activation was blocked by dominant-negative RAS, indicating that WNT3a might act upstream of RAS. WNT3a-induced ERK pathway activations were blocked by AG1478, the epidermal growth factor receptor (EGFR) inhibitor, and EGFR siRNA. The WNT3a-induced ERK pathway activation was not observed in fibroblasts retaining defective EGFR, but the WNT3a effect was restored by EGFR reconstitution. These results indicate involvement of EGFR in the WNT3a-induced ERK pathway activation. WNT3a-induced motility and cytoskeletal rearrangement as well as proliferation of NIH3T3 cells were blocked by AG1478 and EGFR siRNA or abolished in EGFR knock-out fibroblasts, indicating involvement of EGFR in those cellular processes. WNT3a-induced ERK pathway activation was not affected by Dickkoff-1 (DKK-1), although WNT3a-induced activations of the WNT/beta-catenin pathway and proliferation were reduced by DKK-1. EGFR is involved in WNT3a-induced proliferation via both routes dependent on and independent of the WNT/beta-catenin pathway. These results indicate that WNT3a stimulates proliferation and motility of NIH3T3 fibroblasts via EGFR-mediated ERK pathway activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Movement / drug effects*
  • Cell Proliferation / drug effects
  • Cytoskeleton / drug effects
  • Cytoskeleton / metabolism
  • Enzyme Activation / drug effects
  • ErbB Receptors / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • NIH 3T3 Cells
  • Quinazolines
  • RNA, Small Interfering / metabolism
  • Tyrphostins / pharmacology
  • Wnt Proteins / pharmacology*
  • Wnt3 Protein
  • Wnt3A Protein
  • beta Catenin / metabolism
  • raf Kinases / metabolism
  • ras Proteins / metabolism


  • Dkk1 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Quinazolines
  • RNA, Small Interfering
  • Tyrphostins
  • Wnt Proteins
  • Wnt3 Protein
  • Wnt3A Protein
  • Wnt3a protein, mouse
  • beta Catenin
  • RTKI cpd
  • ErbB Receptors
  • raf Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • ras Proteins