Description
Neural cell adhesion molecule L1 (NCAM-L1; also L1-CAM, L1, and CD171) is a 200-220kD type I transmembrane glycoprotein of the immunoglobulin superfamily and L1/neurofascin/NgCAM family. NCAM-L1 is expressed by neurons, especially by growing axons on their growth cones. Non-neuronal cells such as Schwann cells, astrocytes, epithelial cells, and cells of myelomonocytic and lymphoid origin also express NCAM-L1. Full length mouse NCAM-L1 is synthesized as a 1260aa precursor that contains a 19aa signal sequence, a 1104aa extracellular domain (ECD), a 23aa transmembrane region, and a 114aa cytoplasmic tail that is highly conserved. The ECD contains six Ig-like C2-type domains, five fibronectin type III domains, and 21 potential sites for N-linked glycosylation. Mouse NCAM-L1 shares 88% aa sequence identity with human NCAM-L1. NCAM-L1 is critical for neural development. Specifically, NCAM-L1 plays a key role in neuronal cell migration, axon outgrowth, axon fasciculation, synaptogenesis, and myelination. NCAM-L1 mediates hemophilic cell-cell interaction but also binds heterophilic ligands like axonin-1, CD24, CD9, neurocan and several integrins. It has been shown that NCAM-L1 can undergo membrane-proximal cleavage by ADAM10 and ADAM17, leading to the release of the soluble extracellular domain and the generation of a membrane-bound stub. Remaining intact, the soluble extracellular domain has been suggested to serve as a substrate for integrin-mediated cell adhesion, thereby stimulating cellular motility and cell migration. It has also been found that NCAM-L1 plays a role in the ontogeny of human tumors and its expression is linked to poor prognosis. Overexpression promotes tumor-cell invasion and motility, growth in nude mice and tumor metastasis. Research shows that proteolytic processing by ADAM10 and presenilin/gamma-secretase is essential for the nuclear signaling of NCAM-L1 in human carcinoma cell lines. Defects in NCAM-L1 are the cause of MASA syndrome (mental retardation, aphasia, shuffling gait and adducted thumbs), which is also known as CRASH syndrome (corpus callosum hypoplasia, psychomotor retardation, adducted thumbs, spastic paraparesis and hydrocephalus