SEMA3Fs

SEMA3F, or Semaphorin-3F, is a secreted member of the class-3 semaphorins, a family of guidance cues that regulate axon pathfinding during development. The protein is encoded by the SEMA3F gene in humans. Like other class-3 semaphorins, SEMA3F functions as a dimer and contains the sema domain required for receptor binding and signal transduction.

Receptors and signaling: SEMA3F signals through a receptor complex that typically includes neuropilin-2 (NRP2) and a plexin-A family member, most commonly Plexin-A3 (PLXNA3). Neuropilins provide high-affinity binding to SEMA3F but lack intrinsic signaling capacity; plexins mediate the intracellular responses that regulate cytoskeleton dynamics and growth cone behavior, producing repulsive guidance.

Biological roles: In the nervous system, SEMA3F guides developing axons and contributes to neural circuit patterning. It also exerts anti-angiogenic activity by repelling endothelial cells and inhibiting VEGF-driven angiogenesis. Additional roles have been described in bone remodeling and immune regulation, with context-dependent effects.

Clinical relevance: Altered expression of SEMA3F has been associated with cancer progression and metastatic potential in several tumor types, including gastric, colorectal, and prostate cancers. In many cases, reduced SEMA3F expression correlates with worse prognosis, and there is interest in harnessing SEMA3F–NRP2–PLXNA3 signaling as a therapeutic strategy to limit angiogenesis and metastasis.

Genetics: The SEMA3F gene is located on chromosome 3p21.3 in humans. It is part of a larger semaphorin gene cluster, and its expression is regulated by developmental cues and epigenetic mechanisms.