EGF receptor is involved in WNT3a-mediated proliferation and motility of NIH3T3 cells via ERK pathway activation.
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.
Kim
Sung-Eun
SE
National Research Laboratory of Molecular Complex Control, Department of Biotechnology, Yonsei University, Seoul 120-749, South Korea.
Choi
Kang-Yell
KY
D000818:Animals; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D041681:NIH 3T3 Cells; D011799:Quinazolines; D034741:RNA, Small Interfering / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology; D051153:Wnt Proteins / Q000494:pharmacology*; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin / Q000378:metabolism; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D011799:Quinazolines; D034741:RNA, Small Interfering; D020032:Tyrphostins; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D051176:beta Catenin; C101044:RTKI cpd; D066246:ErbB Receptors; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins