| Calponin 3 (CNN3) is an F‑actin–binding calponin family member expressed in smooth muscle and a broad range of non‑muscle cells, where it associates with actin stress fibers and cortical actin to modulate cytoskeletal organization, contractility, and motility. The protein contains an N‑terminal calponin homology–like region and multiple CLIK repeats that provide high‑affinity binding to F‑actin and other thin‑filament components, positioning CNN3 along actin filaments in a manner analogous to other calponins but with distinct expression and regulatory features that tailor its function to non‑muscle contexts. CNN3 is required for efficient actin cytoskeletal rearrangement during processes such as wound closure and invasion; loss of CNN3 reduces stress fiber formation, alters cell shape, and diminishes migration, while CNN3 enrichment at the leading edge coincides with dynamic actin remodeling. In colon cancer and osteosarcoma models, CNN3 promotes invasion and chemoresistance through effects on actin organization and signaling: knockdown decreases invasion through Matrigel, reduces lamellipodia formation, and sensitizes cells to doxorubicin, whereas CNN3 overexpression increases invasive behavior and drug resistance, linking its actin‑regulatory role to metastatic potential and survival under chemotherapeutic stress. CNN3 also modulates Rho family and PI3K–AKT signaling, with CNN3 depletion lowering AKT phosphorylation and downstream survival signaling, and CNN3 expression correlating with activation of pathways that support cytoskeletal plasticity and stress adaptation. In non‑small cell lung cancer, CNN3 expression is reduced relative to normal bronchial epithelial cells, and enforced CNN3 overexpression suppresses proliferation, migration, and invasion, induces G1 arrest and apoptosis, and decreases PI3K and AKT phosphorylation, indicating a context‑dependent role in which CNN3 can act as a negative regulator of PI3K–AKT signaling and motility in certain tumor types. |
