Abstract
The Wnt-beta-catenin canonical signaling pathway is crucial for normal embryonic development, and aberrant expression of components of this pathway results in oncogenesis. Upon scanning for the mitogen-activated protein kinase (MAPK) pathways that might intersect with the canonical Wnt-beta-catenin signaling pathway in response to Wnt3a, we observed a strong activation of p38 MAPK in mouse F9 teratocarcinoma cells. Wnt3a-induced p38 MAPK activation was sensitive to siRNAs against Galpha(q) or Galpha(s), but not against either Galpha(o) or Galpha(11). Activation of p38 MAPK is critical for canonical Wnt-beta-catenin signaling. Chemical inhibitors of p38 MAPK (SB203580 or SB239063) and expression of a dominant negative-version of p38 MAPK attenuate Wnt3a-induced accumulation of beta-catenin, Lef/Tcf-sensitive gene activation, and primitive endoderm formation. Furthermore, epistasis experiments pinpoint p38 MAPK as operating downstream of Dishevelleds. We also demonstrate that chemical inhibition of p38 MAPK restores Wnt3a-attenuated GSK3beta kinase activity. We demonstrate the involvement of G-proteins and Dishevelleds in Wnt3a-induced p38 MAPK activation, highlighting a critical role for p38 MAPK in canonical Wnt-beta-catenin signaling.
Highlights
Wnt signaling is critical for normal embryonic development, patterning, cellular proliferation and homeostasis, and its aberrant activity is linked to many forms of prevalent human carcinomas (Logan and Nusse, 2004; Moon et al, 2002; Moon et al, 2004; Polakis, 2000)
In the absence of Wnt, cellular β-catenin is subjected to proteasome-mediated degradation by the destruction complex, which includes among other proteins Axin and the product of the adenomatous polyposis coli gene (APC)
Upon Wnt3a stimulation, F9 cells differentiate into primitive endoderm, which is characteristic of early mouse development
Summary
Wnt signaling is critical for normal embryonic development, patterning, cellular proliferation and homeostasis, and its aberrant activity is linked to many forms of prevalent human carcinomas (Logan and Nusse, 2004; Moon et al, 2002; Moon et al, 2004; Polakis, 2000). In the absence of Wnt, cellular β-catenin is subjected to proteasome-mediated degradation by the destruction complex, which includes among other proteins Axin and the product of the adenomatous polyposis coli gene (APC). These proteins facilitate the phosphorylation of βcatenin by the Ser/Thr protein kinase glycogen synthase kinase 3β (GSK3β). This leads to ubiquitylation and proteasomemediated degradation of β-catenin. Wnt3a binding to Fz1 leads to activation of the G-proteins Gαo and Gαq and of the phosphoprotein Dishevelled, resulting in reduced GSK3β activity and increased accumulation of β-catenin. Aberrant accumulation of β-catenin contributes to tumorigenesis and requires strict regulation
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