Anaplastic lymphoma kinase
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Anaplastic lymphoma kinase
| Anaplastic lymphoma receptor tyrosine kinase | |||||||||||||
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 Rendering based on PDB 2KUP. |
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| Identifiers | |||||||||||||
| Symbols | ALK; CD246; NBLST3 | ||||||||||||
| External IDs | OMIM: 105590 MGI: 103305 HomoloGene: 68387 GeneCards: ALK Gene | ||||||||||||
| EC number | 2.7.10.1 | ||||||||||||
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| RNA expression pattern | |||||||||||||
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| More reference expression data | |||||||||||||
| Orthologs | |||||||||||||
| Species | Human | Mouse | |||||||||||
| Entrez | 238 | 11682 | |||||||||||
| Ensembl | ENSG00000171094 | ENSMUSG00000055471 | |||||||||||
| UniProt | Q9UM73 | P97793 | |||||||||||
| RefSeq (mRNA) | NM_004304 | NM_007439.2 | |||||||||||
| RefSeq (protein) | NP_004295 | NP_031465.2 | |||||||||||
| Location (UCSC) | Chr 2: 29.42 – 30.14 Mb |
Chr 17: 72.22 – 72.95 Mb |
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| PubMed search | [1] | [2] | |||||||||||
Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246) is an enzyme that in humans is encoded by the ALK gene.[1][2]
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Contents
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Function
ALK plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system.[2]
The deduced amino acid sequences reveal that ALK is a novel receptor tyrosine kinase having a putative transmembrane domain and an extracellular domain. These sequences are absent in the product of the transforming NPM-ALK gene. ALK shows the greatest sequence similarity to LTK (leukocyte tyrosine kinase).
Pathology
The ALK gene can be oncogenic in two ways – first, by forming a fusion gene with any of several other genes, and second, with mutations of the actual DNA code for the gene itself.
Anaplastic large-cell lymphoma
The 2;5 chromosomal translocation is associated with approximately 60% anaplastic large-cell lymphomas (ALCLs). The translocation creates a fusion gene consisting of the ALK (anaplastic lymphoma kinase) gene and the nucleophosmin (NPM) gene: the 3' half of ALK, derived from chromosome 2, is fused to the 5' portion of NPM from chromosome 5. The product of the NPM-ALK fusion gene is oncogenic.
Non-small-cell lung cancer
The EML4-ALK fusion gene is responsible for approximately 3-5% of non-small-cell lung cancer(NSCLC). The vast majority of cases are adenocarcinomas. The standard test used to detect this gene in tumor samples is fluorescence in situ hybridization (FISH), but other techniques such as immunohistochemistry (IHC) and reverse-transcriptase PCR (RT-PCR) can also be used to detect lung cancers with an ALK gene fusion. ALK lung cancers are found in patients of all ages, although on average these patients may be somewhat younger. ALK lung cancers are more common in never or light cigarette smokers, but a significant number of patients with this disease are current or former cigarette smokers.
Familial neuroblastoma
Recent study shows that mutation of ALK "are linked to 10-15% of "neuroblastoma", a deadly childhood form of cancer.[3]
Gene rearrangements in tumours
Treatment
Xalkori (crizotinib), produced by Pfizer, was approved by the FDA for treatment of late stage lung cancer on August 26, 2011.[4] Early results of an initial Phase I trial with 82 patients with ALK induced lung cancer showed a overall response rate of 57%, a disease control rate at 8 weeks of 87% and progression free survival at 6 months of 72%.
See also
References
- ^ Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL, Look AT (Apr 1994). "Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma". Science 263 (5151): 1281–4. doi:10.1126/science.8122112. PMID 8122112.
- ^ a b "Entrez Gene: ALK anaplastic lymphoma kinase (Ki-1)". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=238.
- ^ Mossé YP, Laudenslager M, Longo L, Cole KA, Wood A, Attiyeh EF, Laquaglia MJ, Sennett R, Lynch JE, Perri P, Laureys G, Speleman F, Kim C, Hou C, Hakonarson H, Torkamani A, Schork NJ, Brodeur GM, Tonini GP, Rappaport E, Devoto M, Maris JM (October 2008). "Identification of ALK as a major familial neuroblastoma predisposition gene". Nature 455 (7215): 930–5. doi:10.1038/nature07261. PMC 2672043. PMID 18724359. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2672043. Lay summary – PRNewswire-USNewswire.
- ^ "Xalkori Approved for Lung Cancer". FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails.
Further reading
- Benharroch D, Meguerian-Bedoyan Z, Lamant L, et al. (1998). "ALK-positive lymphoma: a single disease with a broad spectrum of morphology". Blood 91 (6): 2076–84. PMID 9490693.
- Pulford K, Lamant L, Espinos E, et al. (2005). "The emerging normal and disease-related roles of anaplastic lymphoma kinase". Cell. Mol. Life Sci. 61 (23): 2939–53. doi:10.1007/s00018-004-4275-9. PMID 15583856.
- Fujimoto J, Shiota M, Iwahara T, et al. (1996). "Characterization of the transforming activity of p80, a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t(2;5)". Proc. Natl. Acad. Sci. U.S.A. 93 (9): 4181–6. doi:10.1073/pnas.93.9.4181. PMC 39508. PMID 8633037. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=39508.
- Iwahara T, Fujimoto J, Wen D, et al. (1997). "Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system". Oncogene 14 (4): 439–49. doi:10.1038/sj.onc.1200849. PMID 9053841.
- Morris SW, Naeve C, Mathew P, et al. (1997). "ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin's lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK)". Oncogene 14 (18): 2175–88. doi:10.1038/sj.onc.1201062. PMID 9174053.
- Bai RY, Dieter P, Peschel C, et al. (1998). "Nucleophosmin-anaplastic lymphoma kinase of large-cell anaplastic lymphoma is a constitutively active tyrosine kinase that utilizes phospholipase C-gamma to mediate its mitogenicity". Mol. Cell. Biol. 18 (12): 6951–61. PMC 109278. PMID 9819383. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=109278.
- Hernández L, Pinyol M, Hernández S, et al. (1999). "TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma producing two structurally different TFG-ALK translocations". Blood 94 (9): 3265–8. PMID 10556217.
- Souttou B, Carvalho NB, Raulais D, Vigny M (2001). "Activation of anaplastic lymphoma kinase receptor tyrosine kinase induces neuronal differentiation through the mitogen-activated protein kinase pathway". J. Biol. Chem. 276 (12): 9526–31. doi:10.1074/jbc.M007333200. PMID 11121404.
- Stoica GE, Kuo A, Aigner A, et al. (2001). "Identification of anaplastic lymphoma kinase as a receptor for the growth factor pleiotrophin". J. Biol. Chem. 276 (20): 16772–9. doi:10.1074/jbc.M010660200. PMID 11278720.
- Simonitsch I, Polgar D, Hajek M, et al. (2001). "The cytoplasmic truncated receptor tyrosine kinase ALK homodimer immortalizes and cooperates with ras in cellular transformation". FASEB J. 15 (8): 1416–8. PMID 11387242.
- Powers C, Aigner A, Stoica GE, et al. (2002). "Pleiotrophin signaling through anaplastic lymphoma kinase is rate-limiting for glioblastoma growth". J. Biol. Chem. 277 (16): 14153–8. doi:10.1074/jbc.M112354200. PMID 11809760.
- Zamo A, Chiarle R, Piva R, et al. (2002). "Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death". Oncogene 21 (7): 1038–47. doi:10.1038/sj.onc.1205152. PMID 11850821.
- Passoni L, Scardino A, Bertazzoli C, et al. (2002). "ALK as a novel lymphoma-associated tumor antigen: identification of 2 HLA-A2.1-restricted CD8+ T-cell epitopes". Blood 99 (6): 2100–6. doi:10.1182/blood.V99.6.2100. PMID 11877285.
- Bonvini P, Gastaldi T, Falini B, Rosolen A (2002). "Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), a novel Hsp90-client tyrosine kinase: down-regulation of NPM-ALK expression and tyrosine phosphorylation in ALK(+) CD30(+) lymphoma cells by the Hsp90 antagonist 17-allylamino,17-demethoxygeldanamycin". Cancer Res. 62 (5): 1559–66. PMID 11888936.
- Hernández L, Beà S, Bellosillo B, et al. (2002). "Diversity of genomic breakpoints in TFG-ALK translocations in anaplastic large cell lymphomas: identification of a new TFG-ALK(XL) chimeric gene with transforming activity". Am. J. Pathol. 160 (4): 1487–94. doi:10.1016/S0002-9440(10)62574-6. PMC 1867210. PMID 11943732. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1867210.
- ten Berge RL, Meijer CJ, Dukers DF, et al. (2002). "Expression levels of apoptosis-related proteins predict clinical outcome in anaplastic large cell lymphoma". Blood 99 (12): 4540–6. doi:10.1182/blood.V99.12.4540. PMID 12036886.
- Cools J, Wlodarska I, Somers R, et al. (2002). "Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor". Genes Chromosomes Cancer 34 (4): 354–62. doi:10.1002/gcc.10033. PMID 12112524.
- Dirks WG, Fähnrich S, Lis Y, et al. (2002). "Expression and functional analysis of the anaplastic lymphoma kinase (ALK) gene in tumor cell lines". Int. J. Cancer 100 (1): 49–56. doi:10.1002/ijc.10435. PMID 12115586.
External links
- MeSH ALK+protein,+human
- ALK Correlations, Experiments, Publications and Clinical Trials
- GeneReviews/NCBI/NIH/UW entry on ALK-Related Neuroblastoma Susceptibility
- OMIM entries on ALK-Related Neuroblastoma Susceptibility
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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