Abstract
The Wnt-beta-catenin pathway controls numerous cellular processes, including differentiation, cell-fate decisions and dorsal-ventral polarity in the developing embryo. Heterotrimeric G-proteins are essential for Wnt signaling, and regulator of G-protein signaling (RGS) proteins are known to act at the level of G-proteins. The functional role of RGS proteins in the Wnt-beta-catenin pathway was investigated in mouse F9 embryonic teratocarcinoma cells. RGS protein expression was investigated at the mRNA level, and each RGS protein identified was overexpressed and tested for the ability to regulate the canonical Wnt pathway. Expression of RGS19 specifically was found to attenuate Wnt-responsive gene transcription in a time- and dose-dependent manner, to block cytosolic beta-catenin accumulation and Dishevelled3 (Dvl3) phosphorylation in response to Wnt3a and to inhibit Wnt-induced formation of primitive endoderm (PE). Overexpression of a constitutively active mutant of Galpha(o) rescued the inhibition of Lef-Tcf-sensitive gene transcription caused by RGS19. By contrast, expression of RGS19 did not inhibit activation of Lef-Tcf gene transcription when induced in response to Dvl3 expression. However, knockdown of RGS19 by siRNA suppressed canonical Wnt signaling, suggesting a complex role for RGS19 in regulating the ability of Wnt3a to signal to the level of beta-catenin and gene transcription.
Highlights
In unstimulated cells, cytosolic levels of the transcriptional coactivator -catenin are tightly regulated by a multiprotein complex that includes glycogen synthase kinase 3 (GSK3), axin and APC (Ikeda et al, 1998; Kishida et al, 1998; Zeng et al, 1997)
We show that RGS19 controls signaling of the Wnt–-catenin pathway
regulator of G-protein signaling (RGS) protein expression in F9 cells: analysis at the mRNA level The expression of RGS family members was investigated in mouse F9 teratocarcinoma (F9) cells
Summary
Cytosolic levels of the transcriptional coactivator -catenin are tightly regulated by a multiprotein complex that includes glycogen synthase kinase 3 (GSK3), axin and APC (product of the adenomatous polyposis coli gene) (Ikeda et al, 1998; Kishida et al, 1998; Zeng et al, 1997). Upon activation of the G-protein by its cognate heptihelical receptor [i.e. a G-protein-coupled receptor (GPCR) such as Fz], GDP is exchanged for GTP by the G␣ subunit, allowing dissociation of the G-G␥ dimer. Both the GTP-bound G␣-subunits and the ‘free’ G-G␥ dimers are available to activate downstream signaling components (Clapham and Neer, 1993), and both have been shown to function in Wnt signaling (Liu et al, 2001; Slusarski et al, 1997). The period of the activation cycle is determined by the hydrolysis of GTP, which terminates the activation
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