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| | Protein domain structure (left) and cleavage sites (right) of L1CAM. NTF, 200 kDa N-terminal cleavage product; CTF1, 32 kDa C-terminal cleavage product; Ig, immunoglobulin like domain; FN, fibronectin like domain (From Fogel et al., 2003 and Maretzky et al., 2005). |
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| Description | L1CAM (L1) is a 200-220 kD glycoprotein and a member of the immunoglobulin superfamily. This type-1 transmembrane protein consists of six immunoglobulin like domains at the amino terminal end of the molecule followed by five fibronectin type III homologous repeats, a single transmembrane region and a short intracellular domain (Moos et al., 1988). Two splicing variants are known encoding for 1257 and 1253 amino acids proteins. |
| Expression | Neural, hematopoietic and transformed epithelial cells. |
| Localisation | Cell surface, extracellular matrix and nucleus (C-terminal fragment). |
| Function | L1 plays a critical role in axon outgrowth and fasciculation, neuronal migration and survival, synaptic plasticity and regeneration after trauma (Maness et al., 2007). L1 can interact with itself (homophilic) but also with a variety of heterophilic ligands such as integrins, CD24, neurocan, neuropilin-1 and other members of the neural cell adhesion family. In many incidences the binding sites in the L1 molecule have been mapped. The RGD site in the sixth Ig domain supports α5β1, αvβ3,5 integrin-mediated cell binding and the first Ig domain can bind to the proteoglycan neurocan or the VEGF-R2-coreceptor neuropilin-1.
Beside its cell surface localization, L1CAM can also be cleaved by several proteases, i.e. the matrix metalloproteinases ADAM10 and ADAM17, metalloprotease PC5A proprotein convertase or by γ-secretases (Maretzky et al., 2005). Soluble L1CAM has been reported to be important for migration of neuronal as well as of tumor cells (Maretzky et al., 2005; Mechtersheimer et al., 2001), and several studies support a role for L1CAM in tumor growth (Arlt et al., 2006), tumor cell invasion, metastasis of melanoma, ovarial and colon cancer (Mechtersheimer et al., 2001; Gavert et al., 2005; Fogel et al., 2003) and chemoresistance (Sebens Müerköster et al., 2007; Stoeck et al., 2007).
L1 transiently activates pp60c-src, phosphoinositide 3-kinase (PI3 kinase), the VAV2 guanine nucleotide exchange factor, the RAC1 GTPase and p21-activated kinase (PAK1) in a pathway culminating in MEK and ERK activation. |
| Homology | NrCAM/BRABO, CHL1, neurofascin; in invertebrates, neuroglian and sax-7. |
| Neural adhesion molecule L1 as a member of the immunoglobulin superfamily with binding domains similar to fibronectin. |
| Moos M, Tacke R, Scherer H, Teplow D, Fruh K, Schachner M. |
| Nature. 1988 Aug 25;334(6184):701-3. |
| PMID 3412448 |
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| Pathological missense mutations of neural cell adhesion molecule L1 affect homophilic and heterophilic binding activities. |
| De Angelis E, MacFarlane J, Du J-S, Yeo G, Hicks R, Rathjen FG, Kenwrick S, Brummendorf T. |
| EMBO J. 1999 Sep 1;18(17):4744-53. |
| PMID 10469653 |
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| Ectodomain shedding of L1 adhesion molecule promotes cell migration by autocrine binding to integrins. |
| Mechtersheimer S, Gutwein P, Agmon-Levin N, Stoeck A, Oleszewski M, Riedle S, Postina R, Fahrenholz F, Fogel M, Lemmon V, Altevogt P. |
| J Cell Biol. 2001 Nov 12;155(4):661-73. |
| PMID 11706054 |
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| L1 expression as a predictor of progression and survival in patients with uterine and ovarian carcinomas. |
| Fogel M, Gutwein P, Mechtersheimer S, Riedle S, Stoeck A, Smirnov A, Edler L, Ben-Arie A, Huszar M, Altevogt P. |
| Lancet. 2003 Sep 13;362(9387):869-75. |
| PMID 13678974 |
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| L1, a novel target of beta-catenin signaling, transforms cells and is expressed at the invasive front of colon cancers. |
| Gavert N, Conacci-Sorrell M, Gast D, Schneider A, Altevogt P, Brabletz T, Ben-Ze'ev A. |
| J Cell Biol. 2005 Feb 14;168(4):633-42. |
| PMID 15716380 |
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| L1 is sequentially processed by two differently activated metalloproteases and presenilin/gamma-secretase and regulates neural cell adhesion, cell migration, and neurite outgrowth. |
| Maretzky T, Schulte M, Ludwig A, Rose-John S, Blobel C, Hartmann D, Altevogt P, Saftig P, Reiss K. |
| Mol Cell Biol. 2005 Oct;25(20):9040-53. |
| PMID 16199880 |
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| Efficient inhibition of intra-peritoneal tumor growth and dissemination of human ovarian carcinoma cells in nude mice by anti-L1-cell adhesion molecule monoclonal antibody treatment. |
| Arlt MJ, Novak-Hofer I, Gast D, Gschwend V, Moldenhauer G, Grunberg J, Honer M, Schubiger PA, Altevogt P, Kruger A. |
| Cancer Res. 2006 Jan 15;66(2):936-43. |
| PMID 16424028 |
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| Neural recognition molecules of the immunoglobulin superfamily: signaling transducers of axon guidance and neuronal migration. |
| Maness PF, Schachner M. |
| Nat Neurosci. 2007 Jan;10(1):19-26. (REVIEW) |
| PMID 17189949 |
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| Drug-induced expression of the cellular adhesion molecule L1CAM confers anti-apoptotic protection and chemoresistance in pancreatic ductal adenocarcinoma cells. |
| Sebens Muerkoster S, Werbing V, Sipos B, Debus MA, Witt M, Grossmann M,Leisner D, Kotteritzsch J, Kappes H, Kloppel G, Altevogt P, Folsch UR, Schafer H. |
| Oncogene. 2007 Apr 26;26(19):2759-68. |
| PMID 17086212 |
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| L1-CAM in a membrane-bound or soluble form augments protection from apoptosis in ovarian carcinoma cells. |
| Stoeck A, Gast D, Sanderson MP, Issa Y, Gutwein P, Altevogt P. |
| Gynecol Oncol. 2007 Feb;104(2):461-9. |
| PMID 17030349 |
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