L1CAM (Neural cell adhesion molecule L1, also known as L1, CD171 and NCAM-L1) is a founding member of the L1 family, Immunoglobulin (Ig) superfamily of molecules (1-4). It was initially described as a 200-230 kDa neural adhesion molecule that likely played a key role in mouse nervous system development (4-6). Subsequent studies have confirmed the adhesive nature of the molecule, and expanded its activities in both neural and nonneural cell types. L1 is now recognized to play a key role in cell migration, adhesion, neurite outgrowth, myelination and neuronal differentiation (1, 7, 8). It does so through a series of cis
interactions that involve multiple copartners and target receptors (1, 3, 6, 8). Cells known to express L1 are varied, and include immature oligodendrocytes (9), CD4+ T cells, B cells and monocytes (10), both motor and sensory Schwann cells (11, 12), intestinal epithelial progenitor cells (12), cerebellar granule and Purkinje cells (5, 13, 14), and multiple tumor cells such as melanoma (15) plus pancreatic duct and lung carcinoma cells (16, 17). Human L1 was first identified as a 215 kDa glycoprotein on the surface of SKNAS neuroblastoma cells (18). Subsequent cloning established its precursor as being 1257 amino acids (aa) in length (19, 20). The molecule is a type I transmembrane (TM) protein that contains an 1101 aa extracellular region (aa 20-1120) plus a 114 aa cytoplasmic domain (aa 1144-1257). The extracellular region possesses six C2-type Ig-like domains (aa 35-607) followed by five fibronectin (FN) type III domains (aa 612-1108). As noted, L1 participates in multiple cis
interactions, and some of these interaction sites have been mapped to select Ig or FN domains. For instance, Ig-like domains #1, 2 and 6 associate with NP-1, L1 (homotypic binding), and various integrins, respectively (21‑23). The latter interaction is mediated by one (in human) or two (in mouse) RGD motifs (23, 24). Other molecules that heterotypically associate with L1 include NCAM, neurocan, CD24 and EGFR. The cytoplasmic tail contains no kinase motifs, but does possess a FIGQY peptide that interacts with ankyrin, and an RSLE sequence that mediates clathrin-associated endocytosis (1). There are two splice variants, one each in the intracellular and extracellular domains. A deletion of RSLE adversely affects endocytosis, while a Leu substitution for aa 26-31 interfers with numerous heterotypic interactions (25, 26). In general, the full-length L1 molecule is a neuron-associated isoform. L1 is known to undergo proteolysis, either by plasmin or ADAMs. This generates soluble isoforms of varying sizes (140-200 kDa) that retain bioactivity, and which can be incorporated into the surrounding ECM (5, 13, 27-30). The membrane fragments (30-80 kDa) undergo further processing, most importantly by gamma -secretase, to generate a soluble 28 kDa intracellular domain. This domain is SUMOylated, and believed to possess an NLS at Lys1147. Upon presumed entry into the nucleus, L1 is posited to activate L1-responsive genes. Human and mouse L1 precursors share 88% aa sequence identity.
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