C o m m e n t a r y2
Divergent functions for Dickkopf-1Dickkopf-1 (DKK-1) was first identified in Xenopus as an extracellular antagonist of canonical Wnt signaling (1), a fundamental pathway that controls cell fate, survival, and proliferation. Aberrant activation of Wnt signaling also drives tumorigenesis in colon, breast, hepatocellular, and many other cancers (2-4). As a Wnt signaling inhibitor, DKK-1 suppresses tumorigenesis in some cancer cells, including renal cell carcinoma (5), breast carcinoma (6), and colon cancer cells (7-9). However, DKK-1 is often elevated in cancers, is associated with aggressive disease, and promotes proliferation in multiple cell types (10, 11), suggesting that DKK-1 also functions independently of Wnt inhibition. In this issue, Kimura and colleagues investigate the molecular events that lead to DKK-1-induced cancer cell proliferation (12). Their work has identified a Wnt-independent signaling role for DKK-1 through interaction with the type-II transmembrane protein cytoskeleton-associated protein 4 (CKAP4; also known as p63, ERGIC-63, or CLIMP-63). These findings also indicate that the DKK-1/CKAP4 interaction represents a promising therapeutic target for cancer.CKAP4 is a DKK-1 receptor that activates AKT signaling DKK family proteins contain two cysteinerich domains (CRDs). The C-terminal CRD (CRD-2) of DKK-1 inhibits Wnt signaling by directly binding to the Wnt coreceptors LRP5/6 (LDL-related proteins 5 and 6), thereby preventing interaction with Wnts, and by binding to the transmembrane protein KREMEN to promote LRP5/6 internalization (11, 13-15). Kimura et al. have now demonstrated that CRD-1 of DKK-1 binds to CKAP4 at the apical surface of epithelial cells (Figure 1 and ref. 12). Furthermore, DKK-1 binds to CKAP4 with high affinity that is comparable to but independent of its interaction with LRP5/6. Upon DKK-1 binding, CKAP4 recruits phosphatidylinositol-3 kinase (PI3K) to its cytoplasmic domain through interaction with the SH3 domain of the p85α subunit of PI3K. Through this mechanism, DKK-1 activates AKT and promotes proliferation. These findings substantially expand our understanding of DKK-1 signaling mechanisms and define a previously unrecognized input to the PI3K/AKT pathway.The findings of Kimura et al. also raise questions about the potential functions of other DKK family members (12). The DKK family comprises four conserved proteins, DKK-1 through -4 (and DKK-like 1, which lacks the CRDs). DKK-1 antagonizes Wnt/β-catenin signaling, activates AKT (as shown here), and may also activate JNK signaling (16); however, the functions of other DKK family members are less well characterized. DKK-2 and -4 antagonize Wnt signaling, similar to DKK-1, but DKK-2 can also activate canonical Wnt signaling depending on the cellular context (11,17). In contrast, DKK-3 positively regulates Wnt signaling (18) and binds to integrin α6b to induce myogenesis in zebrafish (19). As Kimura and colleagues point out (12), CRD-1 is highly conserved among the four Dkk genes, raising the possib...