DKKs

DKKs, or Dickkopf proteins, are a family of secreted modulators of the Wnt/beta-catenin signaling pathway. The family comprises four members: DKK1, DKK2, DKK3, and DKK4. They function primarily as extracellular antagonists of canonical Wnt signaling by binding to the co-receptors LRP5 and LRP6, often in conjunction with the transmembrane proteins Kremen1 and Kremen2. The resulting complex promotes internalization and removal of LRP5/6 from the cell surface, thereby inhibiting Wnt signal transduction. Most DKK proteins contain an N-terminal signal peptide and two cysteine-rich domains.

In development and adult tissue, DKKs regulate cell fate, proliferation, and organogenesis, including limb patterning, bone formation, and dental development. Dysregulation of DKKs is linked to diseases such as osteoporosis, cancer, and fibrotic conditions, making them potential therapeutic targets.

DKK1 is the best-studied member and is a potent Wnt antagonist. It is involved in embryonic axis formation and postnatal bone remodeling; elevated DKK1 is associated with osteoporosis and osteolytic metastases in cancer. DKK2 modulates Wnt signaling and can act as either an antagonist or, in some contexts, a co-activator; it participates in tooth and bone development. DKK3 shows more variable activity, often described as a modulator with tumor-suppressor–like properties in several cancers, though its role is context dependent. DKK4 inhibits Wnt signaling and has been implicated in intestinal and hair follicle development as well as cancer.

Because of their central role in Wnt regulation, DKK family members are investigated as biomarkers and targets for therapies in bone disease, cancer, and fibrotic disorders.