L1 (protein)
L1CAM | |||
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Identifiers | |||
Gene ontology | |||
Molecular function | |||
Cellular component | |||
Biological process |
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Sources:Amigo / QuickGO |
Ensembl | |||||||||
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UniProt | |||||||||
RefSeq (mRNA) | |||||||||
RefSeq (protein) |
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Location (UCSC) | Chr X: 153.86 – 153.89 Mb | Chr X: 72.9 – 72.94 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
L1, also known as L1CAM, is a
Mutations in the L1 protein are the cause of L1 syndrome, sometimes known by the acronym CRASH (corpus callosum hypoplasia, retardation, aphasia, spastic paraplegia and hydrocephalus).[6]
Tissue and cellular distribution
L1 protein is located all over the nervous system on the surface of neurons. It is placed along the cellular membrane so that one end of the protein remains inside the nerve cell while the other end stays on the outer surface of the neurone. This position allows the protein to activate chemical signals which spread through the neurone.[7]
There are a wide variety of cells which express the protein L1, not only neuronal cells but also some non-neuronal ones.
L1CAM is also frequently used as a marker of Extracellular Vesicles (EVs) originating from neuronal cells, although its presence specifically on neuron-derived EVs is debatable.[9]
Gene
The human L1CAM gene is found in X chromosome regions that are implicated in different neuromuscular diseases, and near the one associated with mental retardation. L1CAM gene is located in the long arm of X chromosome in Xq28 position.[10][11]
Structure
Function
L1 is an important protein for the development of the nervous system affecting both cell adhesion and motility.
Cell adhesion
L1 has a static function as a
Cell motility
Motility promoting functions are related to the regulation of the movement of nerve cells during
Some studies have proved that L1 has a role in tumor growth, tumor cell invasion, metastasis of melanoma, ovarian and colon cancer[15] due to an overexpression of the protein L1 that improves cell motion of the malignant cells.
The domains of this protein promote homophilic interactions, where adhesion molecules on one cell interact with identical molecules on the other cell. And also heterophilic interactions, where an adhesion molecule on one cell works as a receptor that connects with a different molecule on the other cell.[16][17] These interactions promote cell adhesion and regulation of signal transduction.
In addition, L1 participates in myelination processes, which are involved in the proliferation of myelin through the nervous system (specifically the progressive myelination of nerve axon fibers), by mediating the elongation of
Nervous system
L1 is involved in neuron-neuron adhesion, neurite fasciculation, outgrowth of neurites, cerebellar granule cell migration, neurite outgrowth on
Furthermore, evidence shows there is a correlation between fetal alcohol spectrum disorder and L1 protein since ethanol inhibits L1-mediated adhesion and neurite outgrowth.[26] Hirschsprung's disease has also been linked to a L1CAM malfunction.[27]
Transcription and synthesis
The gene that regulates L1CAM transcription is found in
Sequences and different isoforms
L1CAM has three different
Length (n aa) | Mass (Da) | Sequence | |
---|---|---|---|
Isoform 1
(fl-L1) |
1,257 | 140,003 | Canonical sequence .
|
Isoform 2
(sh-L1) |
1,253 | 139,517 | Differs from the canonical sequence in the amino acids between position 1177 and 1180, which aren't found in this isoform.
|
Isoform 3 | 1,248 | 138,908 | Differs from the |
Interactions
L1 (protein) has been shown to
Ig-like domain interactions
L1CAM is capable of folding into a horseshoe configuration by the establishment of homophilic interactions within Ig-like domains of the same protein (the first and the second Ig motifs folding back onto the 4th and 3rd motifs). This conformation is essential for L1CAM being able to interact with other molecules and subsequently performing some of its most important functions.
Ig-like domains are implicated in many homophilic interactions with other L1CAM proteins located in adjacent cells. L1CAM molecules interact via the Ig (1-4)-like domains, allowing cell to cell adhesion. They are also important in the formation of heterophilic interactions with
The six Ig motif of the L1 protein contains an Arg-Gly-Asp sequence which allows binding with diverse surface cell integrins. This interaction leads to a signaling cascade which activates focal adhesion kinases (FAK) which are then converted to its active state and form the FAK/SRC complex. The latest functions as an activator of mitogen-activated protein kinases. Another function derived from integrin binding is the activation of NF-κB which results in making cells more motile and invasive.[5]
Fibronectin domain interactions
Fibronectin domains of L1 protein are also capable of binding cell surface integrins. They interact with fibroblast growth factor receptor 1, which suggests it may be linked to the modulating of neuronal differentiation.[5]
Cytoplasmic tail interactions
The most important binding partners of the cytoplasmic tail of L1 proteins are ankyrins. The interaction is held in high-affinity binding sites located within the so-called “ank repeats” also known as membrane-binding domains.[5] This interaction allows L1 protein connect with the cell's cytoskeleton. Also, L1 protein cytoplasmic tail can bind adaptor 2 (ADP), a key component of clathrin mediated endocytosis.
The fact this region contains some phosphorylation sites suggests L1 may be subject to regulation by kinases.[5]
Implications in cancer metastasis
L1CAM protein expression is normally restricted to neurons. However, it has been noticed there's L1CAM overexpression in all types of cancer cells, which has been associated with poor prognosis, tumor progression and metastasis.[37] This up-regulation may not be necessarily associated with mutations in L1 transcription factors. It has been seen this protein plays a key role in inflammatory reactions as the ones taking place in the tissue surrounding a tumor. This could explain why this protein gets suddenly overproduced in tumor cells. L1CAM's diverse functions make tumor cells more aggressive and resistant. Their migratory and motility related functions may result key in cell epithelial–mesenchymal transition (EMT) allowing cells to lose cell to cell static junctions and apico-basal polarity leading to them becoming migratory and independent. Also, its capacity to form adhesive interactions within different cell types may result in an advantage for tumor cells when it comes to co-opt and invade the surrounding tissues or capillaries.
Once tumor cells become anchorage-independent and migratory, due to L1 up-regulation, they leave the tissue where they belong and migrate through the capillaries to other organs. One frequent destination of tumor cells is the brain. So to settle in the brain, tumor cells have to succeed in crossing the blood brain barrier (BBB) where they get exposed to the plasmin secreted by astrocytes. Plasmin breaks L1CAM and inhibits the malignant cell's migrating powers. However, recent studies have noted these cancer cells overproduce anti-PA serpins, which are the usual inhibitors of plasmin, allowing them to cross the BBB and succeed in metastasis.[37]
Possible therapies involving L1CAM
Because L1CAM is considered to be a key factor in
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000198910 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031391 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ PMID 27267927.
- ^ "Entrez Gene: L1CAM L1 cell adhesion molecule".
- ^ "L1CAM gene". Genetics Home Reference. U.S. Department of Health and Human Services.
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- ^ "L1CAM Mutation Web Page". L1CAM Mutation Database. University Medical Center Groningen. 12 October 2012. Retrieved 23 October 2016.
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- PMID 12957823.
- ^ "L1CAM (L1 cell adhesion molecule)".
- ^ Cushier A. "Cell interactions". University of Malta. Retrieved 2 October 2016.
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- ^ "L1CAM (L1 cell adhesion molecule)". Atlas of Genetics and Cytogenetics in Oncology and Hematology l. Retrieved 6 October 2016.[permanent dead link]
- ^ "L1CAM Gene". Gene Cards.
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- ^ "L1CAM - Neural cell adhesion molecule L1 precursor - Homo sapiens (Human) - L1CAM gene & protein". www.uniprot.org. Retrieved 2016-10-23.
- S2CID 5448318.
- ^ "L1CAM - Neural cell adhesion molecule L1 precursor - Homo sapiens (Human) - L1CAM gene & protein". UniProt. Retrieved 2016-10-23.
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- ^ PMID 24581498.
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Further reading
- Fransen E, Lemmon V, Van Camp G, Vits L, Coucke P, Willems PJ (1996). "CRASH syndrome: clinical spectrum of corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraparesis and hydrocephalus due to mutations in one single gene, L1". European Journal of Human Genetics. 3 (5): 273–84. S2CID 152852.
- Bearer CF (October 2001). "L1 cell adhesion molecule signal cascades: targets for ethanol developmental neurotoxicity". Neurotoxicology. 22 (5): 625–33. PMID 11770884.
- Rosenthal A, Jouet M, Kenwrick S (October 1992). "Aberrant splicing of neural cell adhesion molecule L1 mRNA in a family with X-linked hydrocephalus". Nature Genetics. 2 (2): 107–12. S2CID 12575351.
- Fryns JP, Spaepen A, Cassiman JJ, van den Berghe H (June 1991). "X linked complicated spastic paraplegia, MASA syndrome, and X linked hydrocephalus owing to congenital stenosis of the aqueduct of Sylvius: variable expression of the same mutation at Xq28". Journal of Medical Genetics. 28 (6): 429–31. PMID 1870106.
- Rosenthal A, MacKinnon RN, Jones DS (October 1991). "PCR walking from microdissection clone M54 identifies three exons from the human gene for the neural cell adhesion molecule L1 (CAM-L1)". Nucleic Acids Research. 19 (19): 5395–401. PMID 1923824.
- Kobayashi M, Miura M, Asou H, Uyemura K (October 1991). "Molecular cloning of cell adhesion molecule L1 from human nervous tissue: a comparison of the primary sequences of L1 molecules of different origin". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1090 (2): 238–40. PMID 1932117.
- Harper JR, Prince JT, Healy PA, Stuart JK, Nauman SJ, Stallcup WB (March 1991). "Isolation and sequence of partial cDNA clones of human L1: homology of human and rodent L1 in the cytoplasmic region". Journal of Neurochemistry. 56 (3): 797–804. S2CID 39994677.
- Wolff JM, Frank R, Mujoo K, Spiro RC, Reisfeld RA, Rathjen FG (August 1988). "A human brain glycoprotein related to the mouse cell adhesion molecule L1". The Journal of Biological Chemistry. 263 (24): 11943–7. PMID 3136168.
- Friedlander DR, Milev P, Karthikeyan L, Margolis RK, Margolis RU, Grumet M (May 1994). "The neuronal chondroitin sulfate proteoglycan neurocan binds to the neural cell adhesion molecules Ng-CAM/L1/NILE and N-CAM, and inhibits neuronal adhesion and neurite outgrowth". The Journal of Cell Biology. 125 (3): 669–80. PMID 7513709.
- Ruiz JC, Cuppens H, Legius E, Fryns JP, Glover T, Marynen P, Cassiman JJ (July 1995). "Mutations in L1-CAM in two families with X linked complicated spastic paraplegia, MASA syndrome, and HSAS". Journal of Medical Genetics. 32 (7): 549–52. PMID 7562969.
- Olive S, Dubois C, Schachner M, Rougon G (November 1995). "The F3 neuronal glycosylphosphatidylinositol-linked molecule is localized to glycolipid-enriched membrane subdomains and interacts with L1 and fyn kinase in cerebellum". Journal of Neurochemistry. 65 (5): 2307–17. S2CID 39142478.
- Jouet M, Moncla A, Paterson J, McKeown C, Fryer A, Carpenter N, et al. (June 1995). "New domains of neural cell-adhesion molecule L1 implicated in X-linked hydrocephalus and MASA syndrome". American Journal of Human Genetics. 56 (6): 1304–14. PMID 7762552.
- Fransen E, Schrander-Stumpel C, Vits L, Coucke P, Van Camp G, Willems PJ (December 1994). "X-linked hydrocephalus and MASA syndrome present in one family are due to a single missense mutation in exon 28 of the L1CAM gene". Human Molecular Genetics. 3 (12): 2255–6. PMID 7881431.
- Jouet M, Rosenthal A, Armstrong G, MacFarlane J, Stevenson R, Paterson J, et al. (July 1994). "X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene". Nature Genetics. 7 (3): 402–7. S2CID 1454095.
External links
- GeneReviews/NCBI/NIH/UW entry on L1 Syndrome
- L1+Cell+Adhesion+Molecule at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
Atlas of genetics and cytogenetics in oncology and haematology: http://atlasgeneticsoncology.org/Genes/L1CAMID44110chXq28.html