NCAM

NCAM, or neural cell adhesion molecule, is a glycoprotein of the immunoglobulin superfamily that mediates cell–cell adhesion in the nervous system. In humans, NCAM1 is the best‑characterized member and is also known as CD56 when detected on natural killer cells and some neural and glial populations. Related proteins NCAM2 and NCAM3 comprise the NCAM family.

NCAM is produced in several isoforms that arise from alternative splicing. The extracellular region typically contains five immunoglobulin-like domains and two fibronectin type III repeats. NCAM1 can be expressed as a glycosylphosphatidylinositol (GPI)-anchored isoform NCAM-120, and as transmembrane isoforms NCAM-140 and NCAM-180, which differ mainly in their cytoplasmic tails and signaling capabilities. The extracellular domain can be post-translationally modified by polysialic acid to form PSA-NCAM, a form that reduces homophilic adhesion and enhances plasticity.

NCAM mediates homophilic interactions (NCAM-NCAM binding) that support neurite outgrowth, axon fasciculation, neuronal migration, and synapse formation and stabilization. It participates in signaling pathways, including interactions with fibroblast growth factor receptors (FGFR) and other co-receptors, which influence growth, differentiation, and synaptic remodeling. PSA-NCAM modulates adhesive properties and is especially abundant during development and in contexts of learning, memory, and neural repair after injury.

Expression of NCAM is prominent in the nervous system, with PSA-NCAM enriched in developing brain and adult neurogenic zones. NCAM1/CD56 is also used as a clinical marker for natural killer cells. Altered NCAM/PSA-NCAM expression has been observed in brain injury, neurodevelopmental and psychiatric conditions, and various cancers, reflecting its role in neural plasticity and cell adhesion.