Semaphorin-5A (SEMA5A)

Semaphorin-5A (SEMA5A) is a member of the semaphorin family, structurally characterized by a sema domain at its N-terminal region and seven thrombospondin type-1 repeats at its C-terminal region, making it unique among semaphorins. SEMA5A exists as both a transmembrane and, upon proteolytic cleavage, as a secreted protein. It acts as a bifunctional guidance cue in nervous system development, exerting both attractive and inhibitory effects on axonal growth in a context-dependent manner by binding distinct glycosaminoglycans: heparan sulfate promotes neuronal growth whereas chondroitin sulfate inhibits it. SEMA5A signals primarily via Plexin-A2 in neurons where it inhibits synaptogenesis and dendritic spine density, and Plexin-B3 in cancer where it affects cell migration and invasiveness, sometimes via the Met and MEK/ERK pathways. Aberrant expression or genetic variation in SEMA5A has been linked to cancer invasiveness, autism spectrum disorders, and rheumatoid arthritis, making it of significant interest as a therapeutic target and disease biomarker. The bifunctional nature and context-dependent effects of SEMA5A represent both a unique mechanistic insight and a therapeutic challenge.

Other names

Semaphorin 5ASEMA5AsemFSema FSemaphorin-FSEMAFsemaphorin-5A

Acts as both an attractive and inhibitory cue for neuronal growth by interacting with proteoglycans (heparan sulfate for attraction, chondroitin sulfate for inhibition). Binds and signals via Plexin-A2 (in neurons), Plexin-B3 (in cancer cell migration). Modulates MEK/ERK pathway or Met receptor tyrosine kinase signaling during cell migration and cancer invasion. Inhibits synaptogenesis and dendritic spine formation through PlexinA2-RasGAP signaling.