L1CAM malfunction in the nervous system and human carcinomas

Abstract

Research over the last 25 years on the cell adhesion molecule L1 has revealed its pivotal role in nervous system function. Mutations of the human L1CAM gene have been shown to cause neurodevelopmental disorders such as X-linked hydrocephalus, spastic paraplegia and mental retardation. Impaired L1 function has been also implicated in the aetiology of fetal alcohol spectrum disorders, defective enteric nervous system development and malformations of the renal system. Importantly, aberrant expression of L1 has emerged as a critical factor in the development of human carcinomas, where it enhances cell proliferation, motility and chemoresistance. This discovery promoted collaborative work between tumour biologists and neurobiologists, which has led to a substantial expansion of the basic knowledge about L1 function and regulation. Here we provide an overview of the pathological conditions caused by L1 malfunction. We further discuss how the available data on gene regulation, molecular interactions and posttranslational processing of L1 may contribute to a better understanding of associated neurological and cancerous diseases.

Fig. 1

L1 domain structure and proteolytic cleavage maps. a Schematic protein domain model of L1. L1 has a relative molecular mass of about 220 kDa and consists of an large extracellular part, possessing six Ig-like (Ig 1–6) and five FNIII 1–5 domains. The extracellular part is linked via a single transmembrane sequence to a short ICD. b The serine proteases PC5A and plasmin constitutively cleave full-length L1 (L1–220) at dibasic residues in the third FNIII-like domain, thereby generating an ectodomain fragment of about 140 kDa (L1–140) and a membrane-retained fragment of about 80 kDa (L1–80). c The serine protease neuropsin cleaves L1 in response to neural activity. Cleavage occurs at a site near the membrane, leading to the release of an ectodomain fragment of about 200 kDa (L1–200). d The metalloprotease ADAM10 cleaves L1 at a site near the membrane, leading to the release of an ectodomain fragment of about 200 kDa (L1–200) and a membrane-retained stub of 32 kDa (L1–32). Cleavage occurs constitutively in cancer cells and is activity-dependent in neuronal cells. e The metalloprotease ADAM17 cleaves L1 at a site near the membrane, leading to the release of an ectodomain fragment of about 200 kDa (L1–200) and a membrane-retained stub of 32 kDa (L1–32). Cleavage can be induced by stimulation by phorbol esters or pervanadate. f Constitutive sequential cleavage of L1. Constitutive L1 cleavage by ADAM10 or ADAM17 is followed by cleavage of the membrane-retained 32 kDa fragment mediated by γ-secretase, leading to the release of an intracellular fragment of about 28 kDa (L1–28)

Fig. 2

L1 interaction and processing. L1 is schematically shown in a horseshoe-shaped conformation in which Ig-like domains one and two fold back to interact with the Ig-like domains three and four. a, b Full-length L1 (L1–220) can bind in cis mode (a) or in trans mode (b) to itself (homophilic) or to integrin binding partners (heterophilic) on the same cells (a) or neighbouring cells (b). c L1 can be cleaved from the cell surface by ectodomain shedding involving ADAM metalloproteases. Soluble L1 of about 200 kDa (L1–200) can bind back to integrins in an autocrine (same cell) or paracrine (another cell) fashion, thereby promoting cell migration, metastasis and angiogenesis. d Constitutive sequential L1 cleavage. Following ectodomain shedding by ADAM, the membrane-retained stub of about 32 kDa (L1–32) can be further cleaved by γ-secretase resulting in the release of a soluble L1-intracellular domain of about 28 kDa (L1–28) into the cytoplasm. The L1–28 fragment undergoes nuclear translocation and is involved in gene regulation