Anaplastic lymphoma kinase

ALK
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2KUP, 2KUQ, 2XB7, 2XBA, 2XP2, 2YFX, 2YHV, 2YJR, 2YJS, 2YS5, 2YT2, 3AOX, 3L9P, 3LCS, 3LCT, 4ANL, 4ANQ, 4ANS, 4CCB, 4CCU, 4CD0, 4CLI, 4CLJ, 4CMO, 4CMT, 4CMU, 4CNH, 4CTB, 4CTC, 4DCE, 4FNW, 4FNX, 4FNY, 4FNZ, 4FOB, 4FOD, 4JOA, 4MKC, 4TT7, 4Z55, 5FTO, 5AAB, 5AAA, 5J7H, 5AA9, 5IUH, 5IUI, 5IMX, 5FTQ, 5A9U, 5IUG, 5AA8, 5AAC
Identifiers
Aliases	ALK, CD246, NBLST3, Anaplastic lymphoma kinase, anaplastic lymphoma receptor tyrosine kinase
External IDs	MGI: 103305 HomoloGene: 68387 GeneCards: ALK
Targeted by Drug
5-chloro-N2-(4-(4-(dimethylamino)-1-piperidinyl)-2-methoxyphenyl)-N4-(2-(dimethylphosphinyl)phenyl)-2,4-pyrimidinediamine, ceritinib, crizotinib[1]
Gene ontology Molecular function • transferase activity • nucleotide binding • protein kinase activity • kinase activity • NF-kappaB-inducing kinase activity • protein binding • identical protein binding • ATP binding • transmembrane receptor protein tyrosine kinase activity • protein tyrosine kinase activity Cellular component • integral component of membrane • membrane • plasma membrane • protein complex • extracellular exosome • integral component of plasma membrane • intracellular Biological process • regulation of apoptotic process • transmembrane receptor protein tyrosine kinase signaling pathway • nervous system development • protein phosphorylation • positive regulation of NF-kappaB transcription factor activity • cell proliferation • protein autophosphorylation • activation of MAPK activity • signal transduction • neuron development • peptidyl-tyrosine phosphorylation • NIK/NF-kappaB signaling • phosphorylation Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	238	11682
Ensembl	ENSG00000171094	ENSMUSG00000055471
UniProt	Q9UM73	P97793
RefSeq (mRNA)	NM_004304	NM_007439
RefSeq (protein)	NP_004295.2	NP_031465.2
Location (UCSC)	Chr 2: 29.19 – 29.92 Mb	Chr 17: 71.87 – 72.6 Mb
PubMed search	[2]	[3]
Wikidata

View/Edit Human

View/Edit Mouse

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.^[4][5]

Function

ALK plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system.^[5]

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.^[6] ALK shows the greatest sequence similarity to LTK (leukocyte tyrosine kinase).

Pathology

The ALK gene can be oncogenic in three ways – by forming a fusion gene with any of several other genes, by gaining additional gene copies or 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 and coding for the catalytic domain, is fused to the 5' portion of NPM from chromosome 5. The product of the NPM-ALK fusion gene is oncogenic. In a smaller fraction of ALCL patients, the 3' half of ALK is fused to the 5' sequence of TPM3 gene, encoding for tropomyosin 3. In rare cases, ALK is fused to other 5' fusion partners, such as TFG, ATIC, CLTC1, TPM4, MSN, ALO17, MYH9.^[7]

Adenocarcinoma of the lung

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) by a US FDA approved kit. Recently Roche Ventana obtained approval in China and European Union countries to test this mutation by immunohistochemistry. Other techniques like reverse-transcriptase PCR (RT-PCR) can also be used to detect lung cancers with an ALK gene fusion but not recommended. ALK lung cancers are found in patients of all ages, although on average these patients tend to be younger. ALK lung cancers are more common in light cigarette smokers or nonsmokers, but a significant number of patients with this disease are current or former cigarette smokers. EML4-ALK-rearrangement in NSCLC is exclusive and not found in EGFR- or KRAS-mutated tumors.^[8]

Gene rearrangements and overexpression in other tumours

• Familial cases of neuroblastoma^[9]
• Inflammatory myofibroblastic tumor^[10][11]
• Adult^[12][13] and pediatric^[14][15] renal cell carcinomas
• Esophageal squamous cell carcinoma^[16][17]
• Breast cancer,^[18] notably the inflammatory subtype^[19]
• Colonic adenocarcinoma^[18]
• Glioblastoma multiforme^[20][21]
• Anaplastic thyroid cancer^[22]

ALK inhibitors

• Xalkori (crizotinib), produced by Pfizer, was approved by the FDA for treatment of late stage lung cancer on August 26, 2011.^[23] Early results of an initial Phase I trial with 82 patients with ALK induced lung cancer showed an overall response rate of 57%, a disease control rate at 8 weeks of 87% and progression free survival at 6 months of 72%.
• Ceritinib was approved by the FDA in April 2014 for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.^[24]
• Entrectinib (RXDX-101) is a selective tyrosine kinase inhibitor developed by Ignyta, Inc., with specificity, at low nanomolar concentrations, for all of three Trk proteins (encoded by the three NTRK genes, respectively) as well as the ROS1, and ALK receptor tyrosine kinases. An open label, multicenter, global phase 2 clinical trial called STARTRK-2 is currently underway to test the drug in patients with ROS1/NTRK/ALK gene rearrangements.

See also

• Cluster of differentiation

References

1. "Drugs that physically interact with ALK tyrosine kinase receptor view/edit references on wikidata".
2. "Human PubMed Reference:".
3. "Mouse PubMed Reference:".
4. Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL, Look AT (Mar 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.
5. "Entrez Gene: ALK anaplastic lymphoma kinase (Ki-1)".
6. Iwahara T, Fujimoto J, Wen D, Cupples R, Bucay N, Arakawa T, Mori S, Ratzkin B, Yamamoto T (Jan 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.
7. Mologni L (Jul 2012). "Inhibitors of the anaplastic lymphoma kinase". Expert Opinion on Investigational Drugs. 21 (7): 985–94. doi:10.1517/13543784.2012.690031. PMID 22612599.
8. Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, et al. (Feb 2011). "International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma". Journal of Thoracic Oncology. 6 (2): 244–85. doi:10.1097/JTO.0b013e318206a221. PMC 4513953. PMID 21252716.
9. 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 (Oct 2008). "Identification of ALK as a major familial neuroblastoma predisposition gene". Nature. 455 (7215): 930–5. doi:10.1038/nature07261. PMC 2672043. PMID 18724359. Lay summary – PRNewswire-USNewswire.
10. Cools J, Wlodarska I, Somers R, Mentens N, Pedeutour F, Maes B, De Wolf-Peeters C, Pauwels P, Hagemeijer A, Marynen P (Aug 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.
11. Lawrence B, Perez-Atayde A, Hibbard MK, Rubin BP, Dal Cin P, Pinkus JL, Pinkus GS, Xiao S, Yi ES, Fletcher CD, Fletcher JA (Aug 2000). "TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors". The American Journal of Pathology. 157 (2): 377–84. doi:10.1016/S0002-9440(10)64550-6. PMC 1850130. PMID 10934142.
12. Sukov WR, Hodge JC, Lohse CM, Akre MK, Leibovich BC, Thompson RH, Cheville JC (Nov 2012). "ALK alterations in adult renal cell carcinoma: frequency, clinicopathologic features and outcome in a large series of consecutively treated patients". Modern Pathology. 25 (11): 1516–25. doi:10.1038/modpathol.2012.107. PMID 22743654.
13. Sugawara E, Togashi Y, Kuroda N, Sakata S, Hatano S, Asaka R, Yuasa T, Yonese J, Kitagawa M, Mano H, Ishikawa Y, Takeuchi K (Sep 2012). "Identification of anaplastic lymphoma kinase fusions in renal cancer: large-scale immunohistochemical screening by the intercalated antibody-enhanced polymer method". Cancer. 118 (18): 4427–36. doi:10.1002/cncr.27391. PMID 22252991.
14. Debelenko LV, Raimondi SC, Daw N, Shivakumar BR, Huang D, Nelson M, Bridge JA (Mar 2011). "Renal cell carcinoma with novel VCL-ALK fusion: new representative of ALK-associated tumor spectrum". Modern Pathology. 24 (3): 430–42. doi:10.1038/modpathol.2010.213. PMID 21076462.
15. Mariño-Enríquez A, Ou WB, Weldon CB, Fletcher JA, Pérez-Atayde AR (Mar 2011). "ALK rearrangement in sickle cell trait-associated renal medullary carcinoma". Genes, Chromosomes & Cancer. 50 (3): 146–53. doi:10.1002/gcc.20839. PMID 21213368.
16. Jazii FR, Najafi Z, Malekzadeh R, Conrads TP, Ziaee AA, Abnet C, Yazdznbod M, Karkhane AA, Salekdeh GH (Nov 2006). "Identification of squamous cell carcinoma associated proteins by proteomics and loss of beta tropomyosin expression in esophageal cancer". World Journal of Gastroenterology. 12 (44): 7104–12. PMID 17131471.
17. Yaakup H, Sagap I, Fadilah SA (Oct 2008). "Primary oesophageal Ki (CD30)-positive ALK+ anaplastic large cell lymphoma of T-cell phenotype". Singapore Medical Journal. 49 (10): e289–92. PMID 18946602.
18. Lin E, Li L, Guan Y, Soriano R, Rivers CS, Mohan S, Pandita A, Tang J, Modrusan Z (Sep 2009). "Exon array profiling detects EML4-ALK fusion in breast, colorectal, and non-small cell lung cancers". Molecular Cancer Research. 7 (9): 1466–76. doi:10.1158/1541-7786.MCR-08-0522. PMID 19737969.
19. Tuma RS (Jan 2012). "ALK gene amplified in most inflammatory breast cancers". Journal of the National Cancer Institute. 104 (2): 87–8. doi:10.1093/jnci/djr553. PMID 22215853.
20. Powers C, Aigner A, Stoica GE, McDonnell K, Wellstein A (Apr 2002). "Pleiotrophin signaling through anaplastic lymphoma kinase is rate-limiting for glioblastoma growth". The Journal of Biological Chemistry. 277 (16): 14153–8. doi:10.1074/jbc.M112354200. PMID 11809760.
21. Stoica GE, Kuo A, Aigner A, Sunitha I, Souttou B, Malerczyk C, Caughey DJ, Wen D, Karavanov A, Riegel AT, Wellstein A (May 2001). "Identification of anaplastic lymphoma kinase as a receptor for the growth factor pleiotrophin". The Journal of Biological Chemistry. 276 (20): 16772–9. doi:10.1074/jbc.M010660200. PMID 11278720.
22. Murugan AK, Xing M (Jul 2011). "Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene". Cancer Research. 71 (13): 4403–11. doi:10.1158/0008-5472.CAN-10-4041. PMC 3129369. PMID 21596819.
23. "Xalkori Approved for Lung Cancer". FDA.
24. "ZYKADIA (ceritinib) capsules, for oral use Initial U.S. Approval: 2014" (PDF). United States Food and Drug Administration.

Further reading

• Benharroch D, Meguerian-Bedoyan Z, Lamant L, Amin C, Brugières L, Terrier-Lacombe MJ, Haralambieva E, Pulford K, Pileri S, Morris SW, Mason DY, Delsol G (Mar 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, Jiang Q, Xue L, Turturro F, Delsol G, Morris SW (Dec 2004). "The emerging normal and disease-related roles of anaplastic lymphoma kinase". Cellular and Molecular Life Sciences. 61 (23): 2939–53. doi:10.1007/s00018-004-4275-9. PMID 15583856.
• Fujimoto J, Shiota M, Iwahara T, Seki N, Satoh H, Mori S, Yamamoto T (Apr 1996). "Characterization of the transforming activity of p80, a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t(2;5)". Proceedings of the National Academy of Sciences of the United States of America. 93 (9): 4181–6. doi:10.1073/pnas.93.9.4181. PMC 39508. PMID 8633037.
• Iwahara T, Fujimoto J, Wen D, Cupples R, Bucay N, Arakawa T, Mori S, Ratzkin B, Yamamoto T (Jan 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, James PL, Kirstein MN, Cui X, Witte DP (May 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, Morris SW, Duyster J (Dec 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". Molecular and Cellular Biology. 18 (12): 6951–61. doi:10.1128/mcb.18.12.6951. PMC 109278. PMID 9819383.
• Hernández L, Pinyol M, Hernández S, Beà S, Pulford K, Rosenwald A, Lamant L, Falini B, Ott G, Mason DY, Delsol G, Campo E (Nov 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 (Mar 2001). "Activation of anaplastic lymphoma kinase receptor tyrosine kinase induces neuronal differentiation through the mitogen-activated protein kinase pathway". The Journal of Biological Chemistry. 276 (12): 9526–31. doi:10.1074/jbc.M007333200. PMID 11121404.
• Simonitsch I, Polgar D, Hajek M, Duchek P, Skrzypek B, Fassl S, Lamprecht A, Schmidt G, Krupitza G, Cerni C (Jun 2001). "The cytoplasmic truncated receptor tyrosine kinase ALK homodimer immortalizes and cooperates with ras in cellular transformation". FASEB Journal. 15 (8): 1416–8. doi:10.1096/fj.00-0678fje. PMID 11387242.
• Zamo A, Chiarle R, Piva R, Howes J, Fan Y, Chilosi M, Levy DE, Inghirami G (Feb 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, Gallo B, Coluccia AM, Lemonnier FA, Kosmatopoulos K, Gambacorti-Passerini C (Mar 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 (Mar 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 Research. 62 (5): 1559–66. PMID 11888936.
• Hernández L, Beà S, Bellosillo B, Pinyol M, Falini B, Carbone A, et al. (Apr 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". The American Journal of Pathology. 160 (4): 1487–94. doi:10.1016/S0002-9440(10)62574-6. PMC 1867210. PMID 11943732.
• ten Berge RL, Meijer CJ, Dukers DF, Kummer JA, Bladergroen BA, Vos W, Hack CE, Ossenkoppele GJ, Oudejans JJ (Jun 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.
• Dirks WG, Fähnrich S, Lis Y, Becker E, MacLeod RA, Drexler HG (Jul 2002). "Expression and functional analysis of the anaplastic lymphoma kinase (ALK) gene in tumor cell lines". International Journal of Cancer. Journal International Du Cancer. 100 (1): 49–56. doi:10.1002/ijc.10435. PMID 12115586.

External links

• ALK protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
• ALK Correlations, Experiments, Publications and Clinical Trials
• GeneReviews/NCBI/NIH/UW entry on ALK-Related Neuroblastoma Susceptibility
• OMIM entries on ALK-Related Neuroblastoma Susceptibility

This article incorporates text from the United States National Library of Medicine, which is in the public domain.