| FMNL2 is a diaphanous‑related formin that functions as an effector and upstream modulator of Rho family GTPases and acts as a central regulator of actin‑dependent processes including cell morphology, motility, invasion, and angiogenesis in epithelial and tumor contexts. The protein contains N‑terminal GTPase‑binding and FH3 regulatory regions, a proline‑rich segment, and C‑terminal FH1 and FH2 actin‑assembly domains that together support autoinhibited dimers which become activated by Rho‑family inputs and then nucleate and elongate unbranched actin filaments at the cortical cytoskeleton and leading edges. FMNL2 is enriched at the cell cortex and protrusive structures where it promotes cortical actin filament dynamics, filopodia formation, and stress‑fiber organization, thereby shaping cell polarity, lamellipodial architecture, and traction forces that drive forward movement and matrix invasion. In colorectal carcinoma, FMNL2 expression is elevated in metastatic cell lines and tumor tissues and functions as a positive regulator of motility and metastasis by enhancing cell migration, invasion through extracellular matrices, and dissemination, linking its actin‑polymerizing capacity to clinically aggressive behavior. FMNL2 integrates with RhoA signaling by directly interacting with the RhoA‑specific GEF LARG and acting upstream of RhoA to promote activation of the RhoA/ROCK axis, which in turn stimulates actin assembly, stress‑fiber formation, and serum response factor–dependent transcription, and this FMNL2–RhoA–ROCK circuit is required for lysophosphatidic acid–induced RhoA activation, actin remodeling, and invasive behavior in colorectal cancer cells. FMNL2 also links cytoskeletal remodeling to pro‑metastatic transcriptional and signaling networks by targeting the NF‑κB inhibitor COMMD10 for ubiquitin‑mediated proteasomal degradation; COMMD10 reduction allows increased nuclear localization and activity of p65 NF‑κB, which supports invasion, metastasis, and poor clinical outcomes in colorectal cancer patients. In the tumor microenvironment, FMNL2 promotes angiogenesis and metastasis of colorectal cancer by using its N‑terminal GBD/FH3 region to bind epidermal growth factor‑like protein 6, facilitating EGFL6 loading into tumor‑derived exosomes and enhancing EGFL6 paracrine signaling toward endothelial cells, where EGFL6 engages the membrane receptor CKAP4 and activates the ERK/MMP pathway to drive endothelial migration and neovascularization. |
