WntCa2

WntCa2, also referred to as Wnt/Ca2+, denotes a noncanonical Wnt signaling pathway in which signaling outcomes are driven by increases in intracellular calcium rather than stabilization of β-catenin. The pathway is typically activated when Wnt ligands such as Wnt5a or Wnt11 engage Frizzled receptors, often with specific co-receptors, and recruit Dishevelled as a central signaling hub.

Activation of WntCa2 begins with the activation of phospholipase C (PLC), which generates IP3 and DAG. IP3 then prompts release of Ca2+ from intracellular stores, raising cytosolic calcium levels. The Ca2+ signals activate a suite of calcium-dependent effectors, including calcineurin, Ca2+/calmodulin-dependent protein kinase II (CaMKII), and conventional protein kinase C (PKC) isoforms. These effectors regulate transcription factors such as NFAT and AP-1 and influence other signaling networks, contributing to diverse cellular responses.

WntCa2 signaling interacts with other pathways, and its relationship with the canonical Wnt/β-catenin pathway is context-dependent. Depending on the cell type and developmental stage, WntCa2 can modulate or be modulated by canonical signaling, illustrating extensive cross-talk between pathways. Dishevelled remains a key integrator in this signaling axis, coordinating effects on cytoskeletal dynamics, cell polarity, and gene expression.

Biologically, WntCa2 participates in embryonic development and tissue morphogenesis, including processes such as cell movement, adhesion, and differentiation in various tissues. In adults, it contributes to tissue homeostasis and regeneration in a context-specific manner. Dysregulation of WntCa2 signaling has been linked to developmental disorders and cancer, with outcomes that can be either tumor-suppressive or tumor-promoting depending on context. Researchers continue to delineate the precise mechanisms and therapeutic implications of this pathway.