The 259-amino acid DKK2 protein, like DKK1, DKK3, and DKK4, possesses an N-terminal signal peptide and 2 conserved cysteine-rich domains, which are separated by a linker region and contain 10 cys residues each. The second cys region has a putative lipid-binding function that may facilitate WNT/DKK interactions at the plasma membrane. The linker region contains 50 to 55 amino acids in DKK1, DKK2, and DKK4, whereas in DKK3 it contains only 12 amino acids. All DKKs have several potential sites for cleavage by furin-type proteases. Northern blot analysis revealed expression of 4.0- and 4.5-kb DKK2 transcripts in heart, brain, skeletal muscle, and lung. Western blot analysis showed that DKK2 is secreted as a 15- to 17-kD protein. Functional analysis determined that DKK2 does not block Xenopus Wnt8 induction of a secondary axis in frog embryos.