PLXNB3 (plexin B3) is an X-linked transmembrane receptor that functions as a semaphorin signaling platform with critical roles in cancer progression and cell migration. Primary function: PLXNB3 acts as a receptor for SEMA5A ligand, mediating axon guidance, cell migration, and invasive growth 12. Mechanism: PLXNB3 binding to SEMA5A activates MET receptor tyrosine kinase, which recruits SRC and focal adhesion kinase, triggering downstream signaling cascades that promote cell migration and invasion 2. In breast cancer, PLXNB3-MET-SRC signaling activates STAT3, a transcription factor that increases NANOG expression and drives breast cancer stem cell specification 2. The SEMA5A-PLXNB3 axis also enhances aerobic glycolysis (Warburg effect) in pancreatic ductal adenocarcinoma metastasis 3. Disease relevance: PLXNB3 expression is upregulated by hypoxia-inducible factor 1 (HIF-1) under intratumoral hypoxia and is highly expressed in estrogen receptor-negative breast cancer, correlating with tumor grade, stage, and patient mortality 1. PLXNB3 is enriched in triple-negative breast cancer and required for cell growth, invasion, and migration 4. Clinical significance: PLXNB3 knockdown impairs tumor formation and lung metastasis in orthotopic breast cancer models 1, positioning PLXNB3 as a potential therapeutic target for aggressive cancers with poor prognosis 43.