DKK1 is a secreted protein that antagonizes Wnt signaling and plays essential 
roles in vertebrate embryogenesis including head induction, skeletal 
development, and limb patterning. DKK1 is also implicated in osteoporosis, 
arthritis, and cancer and represents a potential therapeutic target for the 
treatment of these diseases. DKK1 is a high affinity antagonistic ligand for 
LRP6, which is a Wnt coreceptor that acts together with the Frizzled serpentine 
receptor to initiate Wnt signal transduction. Two different models have been 
proposed to account for the mechanism by which DKK1 antagonizes LRP6 function. 
One model suggests that DKK1 binding to LRP6 disrupts Wnt-induced Frizzled-LRP6 
complex formation, whereas the other model proposes that DKK1 interaction with 
LRP6 promotes LRP6 internalization and degradation, thereby reducing the cell 
surface LRP6 level. To clarify the molecular basis of DKK1 action, we examined 
how DKK1 affects the endogenous LRP6 in several mammalian cell lines including 
mouse embryonic fibroblasts. Here we show that DKK1 inhibits Wnt signaling but 
induces neither LRP6 down-regulation from the cell surface nor reduction of 
total LRP6 protein level and that DKK1 has no effect on the rate of continuous 
internalization of LRP6 and the half-life (about 4.7 h) of LRP6. We conclude 
that DKK1 inhibition of LRP6 is independent of LRP6 internalization and 
degradation.