O32. Wnt5a: Its signaling, cellular functions, and diseases

Abstract

The genetics of cancer and development have converged in the identification of intra- and extra-cellular signaling pathways that are aberrantly regulated in cancer and are also central to embryonic pattering. The Wnt signaling pathway has provided an outstanding example of this. Wnt proteins are secreted molecules and Wnts activate multiple intracellular signaling systems. The b-catenin-dependent pathway that is most extensively studied is known to regulate cellular proliferation and differentiation. Genetic alterations of proteins that constitute this pathway are often observed in human cancer. Some Wnts activate the b-catenin-independent pathway that modulates cell movement and polarity, as first observed during embryogenesis. However, how the b-catenin-independent pathway regulates these cellular functions or whether the abnormal activation of this pathway is involved in tumorigenesis is not clear. Since Wnt5a is a representative ligand that activates the b-catenin-independent pathway, we analyzed the molecular mechanism by which Wnt5a activates signaling pathway, regulates cell adhesion and migration, and affects aggressiveness of cancers. We found that Wnt5a activates Rac through clathrin-dependent receptor endocytosis. Knockdown of Wnt5a reduced the dynamics of focal adhesion turnover and suppressed cell migration activities. Dvl and APC formed a complex with each other, and Wnt5a enhanced the complex formation. Dvl and APC bound to FAK (focal adhesion kinase) and paxillin, respectively, and Dvl and APC were necessary for cell-to-substrate adhesion-dependent activation of FAK and phosphorylation of paxillin. Furthermore, Wnt5a receptor Fz2 and integrin were present closely on substrate-facing surface of cells. These results suggest that Wnt5a and integrin signaling cooperate to regulate cell adhesion and migration. Immunohistochmical analyses revealed that Wnt5a is overexpressed in about 30% of gastric cancer samples. The positivity of Wnt5a expression was correlated with advanced stages and poor prognosis of gastric cancer. Knockdown of Wnt5a in gastric cancer cells suppressed their metastatic ability in nude mice. These results suggest that Wnt5a is a good therapeutic target for gastric cancer. In this seminar, we will discuss about our recent observations in the functions and mechanisms of the Wnt5a/b-catenin-independent pathway with an emphasis on its functional contribution to tumor progression.