Wnt signaling is known to be important for diverse embryonic and post-natal 
cellular events and be regulated by the proteins Dishevelled and Axin. Although 
Dishevelled is activated by Wnt and involved in signal transduction, it is not 
clear how Dishevelled-mediated signaling is turned off. We report that guanine 
nucleotide binding protein beta 2 (Gnb2; Gbeta2) bound to Axin and Gbeta2 
inhibited Wnt mediated reporter activity. The inhibition involved reduction of 
the level of Dishevelled, and the Gbeta2gamma2 mediated reduction of Dishevelled 
was countered by increased expression of Axin. Consistent with these effects in 
HEK293T cells, injection of Gbeta2gamma2 into Xenopus embryos inhibited the 
formation of secondary axes induced either by XWnt8 or Dishevelled, but not by 
beta-catenin. The DEP domain of Dishevelled is necessary for both interaction 
with Gbeta2gamma2 and subsequent degradation of Dishevelled via the lysosomal 
pathway. Signaling induced by Gbeta2gamma2 is required because a mutant of 
Gbeta2, Gbeta2 (W332A) with lower signaling activity, had reduced ability to 
downregulate the level of Dishevelled. Activation of Wnt signaling by either of 
two methods, increased Frizzled signaling or transient transfection of Wnt, also 
led to increased degradation of Dishevelled and the induced Dishevelled loss is 
dependent on Gbeta1 and Gbeta2. Other studies with agents that interfere with 
PLC action and calcium signaling suggested that loss of Dishevelled is mediated 
through the following pathway: Wnt/Frizzled-->Gbetagamma-->PLC-->Ca(+2)/PKC 
signaling. Together the evidence suggests a novel negative feedback mechanism in 
which Gbeta2gamma2 inhibits Wnt signaling by degradation of Dishevelled.