Wingless-type MMTV integration site family member (Wnt)

Wnt signaling proteins are a family of 19 secreted glycoproteins in humans that orchestrate critical cellular processes including proliferation, differentiation, and migration (Nusse & Clevers, 2017, Cell). These proteins function as ligands that bind to Frizzled receptors and LRP5/6 co-receptors, initiating the canonical beta-catenin pathway or non-canonical pathways like the planar cell polarity (PCP) and Wnt/calcium pathways (Komiya & Habas, 2008, Organogenesis). In healthy adults, Wnt signaling is essential for the maintenance of stem cell populations in tissues such as the gut, skin, and bone marrow (Clevers et al., 2014, Science). Aberrant activation of Wnt signaling is strongly linked to various cancers, particularly colorectal cancer, where it drives uncontrolled cell growth (Zhan et al., 2017, Oncogene). Therapeutic interventions targeting Wnt proteins often focus on inhibiting Porcupine, an O-acyltransferase required for Wnt secretion, or using biologics to block receptor interactions (Liu et al., 2013, PNAS). However, because Wnt signaling is vital for normal tissue regeneration, drug development faces significant hurdles regarding dose-limiting toxicities in the bone and gastrointestinal tract (Kahn, 2014, Nat Rev Drug Discov).

Other names

Wnt familyWnt signaling proteinsWingless-related integration site

Drugs targeting Wnt signaling proteins primarily act by inhibiting Porcupine (PORCN), an endoplasmic reticulum-resident O-acyltransferase required for the palmitoylation and subsequent secretion of all Wnt ligands (Liu et al., 2013, PNAS). Other mechanisms include the use of monoclonal antibodies to block the interaction between Wnt ligands and Frizzled receptors, or the use of decoy receptors (Frizzled-Fc fusion proteins) to sequester Wnt ligands (Gurney et al., 2012, PNAS).