SEMA5B (Semaphorin 5B) is a transmembrane protein with dual roles in neural development and cancer progression. In the nervous system, SEMA5B functions as a guidance cue that regulates synapse elimination and formation in hippocampal neurons through proteolytic processing of its semaphorin domain 1. The protein is cleaved by ADAM-17 and potentially other proteases to release soluble ectodomain fragments that act as repulsive growth cone guidance signals 2. SEMA5B is also essential for proper sensory neuron development, with its expression regulated by MECP2 in trigeminal ganglia 3. In cancer contexts, SEMA5B functions as an oncogene across multiple tumor types. In esophageal squamous cell carcinoma, SEMA5B promotes glycolysis by stabilizing VDAC2 protein and suppressing NEDD4-mediated degradation, enhancing cell proliferation and migration 4. In clear cell renal carcinoma, SEMA5B is a HIF-2α target gene that is suppressed by PRDM16-mediated epigenetic silencing, with restoration of PRDM16 blocking tumor growth 5. SEMA5B expression is significantly elevated in gastric adenocarcinoma and correlates with poor prognosis through activation of malignant tumor, MAPK, and Notch signaling pathways 6. SEMA5B also serves as a prognostic biomarker in Burkitt lymphoma 7.