Anaplastic lymphoma kinase: Difference between revisions

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{{Infobox_gene}}
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'''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]].<ref name="pmid8122112">{{cite journal | vauthors = Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL, Look AT | title = Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma | journal = Science | volume = 263 | issue = 5151 | pages = 1281–4 | date = Mar 1994 | pmid = 8122112 | pmc =  | doi = 10.1126/science.8122112 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: ALK anaplastic lymphoma kinase (Ki-1)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=238| accessdate = }}</ref>
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{GNF_Protein_box
| image =
| image_source =
| PDB =
| Name = Anaplastic lymphoma kinase (Ki-1)
| HGNCid = 427
| Symbol = ALK
| AltSymbols =; CD246; TFG/ALK
| OMIM = 105590
| ECnumber = 
| Homologene = 68387
| MGIid = 103305
| GeneAtlas_image1 = PBB_GE_ALK_208211_s_at_tn.png
| GeneAtlas_image2 = PBB_GE_ALK_208212_s_at_tn.png
| Function = {{GNF_GO|id=GO:0000166 |text = nucleotide binding}} {{GNF_GO|id=GO:0004714 |text = transmembrane receptor protein tyrosine kinase activity}} {{GNF_GO|id=GO:0004716 |text = receptor signaling protein tyrosine kinase activity}} {{GNF_GO|id=GO:0004872 |text = receptor activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0005524 |text = ATP binding}} {{GNF_GO|id=GO:0016740 |text = transferase activity}}
| Component = {{GNF_GO|id=GO:0005887 |text = integral to plasma membrane}} {{GNF_GO|id=GO:0016020 |text = membrane}}
| Process = {{GNF_GO|id=GO:0006468 |text = protein amino acid phosphorylation}} {{GNF_GO|id=GO:0006487 |text = protein amino acid N-linked glycosylation}} {{GNF_GO|id=GO:0007169 |text = transmembrane receptor protein tyrosine kinase signaling pathway}} {{GNF_GO|id=GO:0007399 |text = nervous system development}} {{GNF_GO|id=GO:0007420 |text = brain development}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 238
    | Hs_Ensembl = ENSG00000171094
    | Hs_RefseqProtein = NP_004295
    | Hs_RefseqmRNA = NM_004304
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 2
    | Hs_GenLoc_start = 29269594
    | Hs_GenLoc_end = 29997029
    | Hs_Uniprot = Q9UM73
    | Mm_EntrezGene = 11682
    | Mm_Ensembl = ENSMUSG00000055471
    | Mm_RefseqmRNA = NM_007439
    | Mm_RefseqProtein = NP_031465
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 17
    | Mm_GenLoc_start = 71774299
    | Mm_GenLoc_end = 72508566
    | Mm_Uniprot = P97793
  }}
}}
'''Anaplastic lymphoma kinase (Ki-1)''', also known as '''ALK''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: ALK anaplastic lymphoma kinase (Ki-1)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=238| accessdate = }}</ref>


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ALK plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system.<ref name="entrez" />
{{PBB_Summary
| section_title =
| summary_text = The 2;5 chromosomal translocation is frequently associated with 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. A recent study shows that the product of the NPM-ALK fusion gene is oncogenic. The deduced amino acid sequences reveal that ALK is a novel receptor protein-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). ALK plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system.<ref name="entrez">{{cite web | title = Entrez Gene: ALK anaplastic lymphoma kinase (Ki-1)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=238| accessdate = }}</ref>
}}


==See also==
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.<ref>{{cite journal | vauthors = Iwahara T, Fujimoto J, Wen D, Cupples R, Bucay N, Arakawa T, Mori S, Ratzkin B, Yamamoto T | title = Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system | journal = Oncogene | volume = 14 | issue = 4 | pages = 439–49 | date = Jan 1997 | pmid = 9053841 | doi = 10.1038/sj.onc.1200849 }}</ref>  ALK shows the greatest sequence similarity to [[LTK (gene)|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 lymphoma]]s (ALCLs). The translocation creates a fusion gene consisting of the ALK (anaplastic lymphoma kinase) gene and the [[NPM1|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, [[Inosine monophosphate synthase|ATIC]], CLTC1, [[TPM4]], MSN, ALO17, [[MYH9]].<ref name="pmid22612599">{{cite journal | vauthors = Mologni L | title = Inhibitors of the anaplastic lymphoma kinase | journal = Expert Opinion on Investigational Drugs | volume = 21 | issue = 7 | pages = 985–94 | date = Jul 2012 | pmid = 22612599 | doi = 10.1517/13543784.2012.690031 }}</ref>
 
=== 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.{{Citation needed|reason=Reliable source requested|date=October 2015}}  Other techniques like reverse-transcriptase PCR (RT-PCR) can also be used to detect lung cancers with an ALK gene fusion but not recommended.{{Citation needed|reason=Reliable source requested|date=October 2015}} 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.<ref name="pmid21252716">{{cite journal | vauthors = Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, Beer DG, Powell CA, Riely GJ, Van Schil PE, Garg K, Austin JH, Asamura H, Rusch VW, Hirsch FR, Scagliotti G, Mitsudomi T, Huber RM, Ishikawa Y, Jett J, Sanchez-Cespedes M, Sculier JP, Takahashi T, Tsuboi M, Vansteenkiste J, Wistuba I, Yang PC, Aberle D, Brambilla C, Flieder D, Franklin W, Gazdar A, Gould M, Hasleton P, Henderson D, Johnson B, Johnson D, Kerr K, Kuriyama K, Lee JS, Miller VA, Petersen I, Roggli V, Rosell R, Saijo N, Thunnissen E, Tsao M, Yankelewitz D | title = International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma | journal = Journal of Thoracic Oncology | volume = 6 | issue = 2 | pages = 244–85 | date = Feb 2011 | pmid = 21252716 | pmc = 4513953 | doi = 10.1097/JTO.0b013e318206a221 | displayauthors = 6 }}</ref>
 
=== Gene rearrangements and overexpression in other tumours ===
*Familial cases of [[neuroblastoma]]<ref name="pmid18724359">{{cite journal | vauthors = 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 | title = Identification of ALK as a major familial neuroblastoma predisposition gene | journal = Nature | volume = 455 | issue = 7215 | pages = 930–5 | date = Oct 2008 | pmid = 18724359 | pmc = 2672043 | doi = 10.1038/nature07261 | laysummary = http://www.prnewswire.com/cgi-bin/micro_stories.pl?ACCT=159681&TICK=CHOP&STORY=/www/story/08-25-2008/0004872713&EDATE=Aug+25,+2008 | laysource = PRNewswire-USNewswire }}</ref>
*[[Inflammatory myofibroblastic tumor]]<ref name="pmid12112524">{{cite journal | vauthors = Cools J, Wlodarska I, Somers R, Mentens N, Pedeutour F, Maes B, De Wolf-Peeters C, Pauwels P, Hagemeijer A, Marynen P | title = Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor | journal = Genes, Chromosomes & Cancer | volume = 34 | issue = 4 | pages = 354–62 | date = Aug 2002 | pmid = 12112524 | doi = 10.1002/gcc.10033 }}</ref><ref name="pmid10934142">{{cite journal | vauthors = Lawrence B, Perez-Atayde A, Hibbard MK, Rubin BP, Dal Cin P, Pinkus JL, Pinkus GS, Xiao S, Yi ES, Fletcher CD, Fletcher JA | title = TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors | journal = The American Journal of Pathology | volume = 157 | issue = 2 | pages = 377–84 | date = Aug 2000 | pmid = 10934142 | pmc = 1850130 | doi = 10.1016/S0002-9440(10)64550-6 }}</ref>
* Adult<ref name="pmid22743654">{{cite journal | vauthors = Sukov WR, Hodge JC, Lohse CM, Akre MK, Leibovich BC, Thompson RH, Cheville JC | title = ALK alterations in adult renal cell carcinoma: frequency, clinicopathologic features and outcome in a large series of consecutively treated patients | journal = Modern Pathology | volume = 25 | issue = 11 | pages = 1516–25 | date = Nov 2012 | pmid = 22743654 | doi = 10.1038/modpathol.2012.107 }}</ref><ref name="pmid22252991">{{cite journal | vauthors = Sugawara E, Togashi Y, Kuroda N, Sakata S, Hatano S, Asaka R, Yuasa T, Yonese J, Kitagawa M, Mano H, Ishikawa Y, Takeuchi K | title = Identification of anaplastic lymphoma kinase fusions in renal cancer: large-scale immunohistochemical screening by the intercalated antibody-enhanced polymer method | journal = Cancer | volume = 118 | issue = 18 | pages = 4427–36 | date = Sep 2012 | pmid = 22252991 | doi = 10.1002/cncr.27391 }}</ref> and pediatric<ref name="pmid21076462">{{cite journal | vauthors = Debelenko LV, Raimondi SC, Daw N, Shivakumar BR, Huang D, Nelson M, Bridge JA | title = Renal cell carcinoma with novel VCL-ALK fusion: new representative of ALK-associated tumor spectrum | journal = Modern Pathology | volume = 24 | issue = 3 | pages = 430–42 | date = Mar 2011 | pmid = 21076462 | doi = 10.1038/modpathol.2010.213 }}</ref><ref name="pmid21213368">{{cite journal | vauthors = Mariño-Enríquez A, Ou WB, Weldon CB, Fletcher JA, Pérez-Atayde AR | title = ALK rearrangement in sickle cell trait-associated renal medullary carcinoma | journal = Genes, Chromosomes & Cancer | volume = 50 | issue = 3 | pages = 146–53 | date = Mar 2011 | pmid = 21213368 | doi = 10.1002/gcc.20839 }}</ref> [[renal cell carcinoma]]s
*[[Esophageal cancer|Esophageal squamous cell carcinoma]]<ref name="pmid17131471">{{cite journal | vauthors = Jazii FR, Najafi Z, Malekzadeh R, Conrads TP, Ziaee AA, Abnet C, Yazdznbod M, Karkhane AA, Salekdeh GH | title = Identification of squamous cell carcinoma associated proteins by proteomics and loss of beta tropomyosin expression in esophageal cancer | journal = World Journal of Gastroenterology | volume = 12 | issue = 44 | pages = 7104–12 | date = Nov 2006 | pmid = 17131471 | doi = 10.3748/wjg.v12.i44.7104 }}</ref><ref name="pmid18946602">{{cite journal | vauthors = Yaakup H, Sagap I, Fadilah SA | title = Primary oesophageal Ki (CD30)-positive ALK+ anaplastic large cell lymphoma of T-cell phenotype | journal = Singapore Medical Journal | volume = 49 | issue = 10 | pages = e289-92 | date = Oct 2008 | pmid = 18946602 | doi =  }}</ref>
* [[Breast cancer]],<ref name="exon">{{cite journal | vauthors = Lin E, Li L, Guan Y, Soriano R, Rivers CS, Mohan S, Pandita A, Tang J, Modrusan Z | title = Exon array profiling detects EML4-ALK fusion in breast, colorectal, and non-small cell lung cancers | journal = Molecular Cancer Research | volume = 7 | issue = 9 | pages = 1466–76 | date = Sep 2009 | pmid = 19737969 | doi = 10.1158/1541-7786.MCR-08-0522 }}</ref> notably the [[inflammatory breast cancer|inflammatory]] subtype<ref name="pmid22215853">{{cite journal | vauthors = Tuma RS | title = ALK gene amplified in most inflammatory breast cancers | journal = Journal of the National Cancer Institute | volume = 104 | issue = 2 | pages = 87–8 | date = Jan 2012 | pmid = 22215853 | doi = 10.1093/jnci/djr553 }}</ref>
* [[Colorectal cancer|Colonic adenocarcinoma]]<ref name=exon />
* [[Glioblastoma multiforme]]<ref name="pmid11809760">{{cite journal | vauthors = Powers C, Aigner A, Stoica GE, McDonnell K, Wellstein A | title = Pleiotrophin signaling through anaplastic lymphoma kinase is rate-limiting for glioblastoma growth | journal = The Journal of Biological Chemistry | volume = 277 | issue = 16 | pages = 14153–8 | date = Apr 2002 | pmid = 11809760 | doi = 10.1074/jbc.M112354200 }}</ref><ref name="pmid11278720">{{cite journal | vauthors = Stoica GE, Kuo A, Aigner A, Sunitha I, Souttou B, Malerczyk C, Caughey DJ, Wen D, Karavanov A, Riegel AT, Wellstein A | title = Identification of anaplastic lymphoma kinase as a receptor for the growth factor pleiotrophin | journal = The Journal of Biological Chemistry | volume = 276 | issue = 20 | pages = 16772–9 | date = May 2001 | pmid = 11278720 | doi = 10.1074/jbc.M010660200 }}</ref>
* [[Anaplastic thyroid cancer]]<ref name="pmid21596819">{{cite journal | vauthors = Murugan AK, Xing M | title = Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene | journal = Cancer Research | volume = 71 | issue = 13 | pages = 4403–11 | date = Jul 2011 | pmid = 21596819 | pmc = 3129369 | doi = 10.1158/0008-5472.CAN-10-4041 }}</ref>
 
== ALK inhibitors ==
{{main article|ALK inhibitor}}
* Xalkori ([[crizotinib]]), produced by Pfizer, was approved by the FDA for treatment of late stage lung cancer on August 26, 2011.<ref>{{cite web|title=Xalkori Approved for Lung Cancer|url=http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails|publisher=FDA}}</ref> 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.<ref name="urlwww.accessdata.fda.gov">{{cite web | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205755s000lbl.pdf | title = ZYKADIA (ceritinib) capsules, for oral use Initial U.S. Approval: 2014 | publisher = United States Food and Drug Administration }}</ref>
* [[Entrectinib]] (RXDX-101) is a selective tyrosine kinase inhibitor developed by Ignyta, Inc., with specificity, at low nanomolar concentrations, for all of three [[Trk receptor|Trk proteins]] (encoded by the three ''NTRK'' genes, respectively) as well as the ROS1, and ALK receptor [[Tyrosine kinase|tyrosine kinases.]] An open label, multicenter, global phase 2 clinical trial called [https://www.startrktrials.com/ STARTRK-2] is currently underway to test the drug in patients with ROS1/[[Tropomyosin receptor kinase A|NTRK]]/ALK gene rearrangements.
 
== See also ==
* [[Cluster of differentiation]]
* [[Cluster of differentiation]]


==References==
== References ==
{{reflist|2}}
{{reflist|2}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
* {{cite journal | vauthors = 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 | title = ALK-positive lymphoma: a single disease with a broad spectrum of morphology | journal = Blood | volume = 91 | issue = 6 | pages = 2076–84 | date = Mar 1998 | pmid = 9490693 | doi =  }}
| citations =
* {{cite journal | vauthors = Pulford K, Lamant L, Espinos E, Jiang Q, Xue L, Turturro F, Delsol G, Morris SW | title = The emerging normal and disease-related roles of anaplastic lymphoma kinase | journal = Cellular and Molecular Life Sciences | volume = 61 | issue = 23 | pages = 2939–53 | date = Dec 2004 | pmid = 15583856 | doi = 10.1007/s00018-004-4275-9 }}
*{{cite journal | author=Benharroch D, Meguerian-Bedoyan Z, Lamant L, ''et al.'' |title=ALK-positive lymphoma: a single disease with a broad spectrum of morphology. |journal=Blood |volume=91 |issue= 6 |pages= 2076-84 |year= 1998 |pmid= 9490693 |doi=  }}
* {{cite journal | vauthors = Fujimoto J, Shiota M, Iwahara T, Seki N, Satoh H, Mori S, Yamamoto T | title = Characterization of the transforming activity of p80, a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t(2;5) | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 9 | pages = 4181–6 | date = Apr 1996 | pmid = 8633037 | pmc = 39508 | doi = 10.1073/pnas.93.9.4181 }}
*{{cite journal | author=Pulford K, Lamant L, Espinos E, ''et al.'' |title=The emerging normal and disease-related roles of anaplastic lymphoma kinase. |journal=Cell. Mol. Life Sci. |volume=61 |issue= 23 |pages= 2939-53 |year= 2005 |pmid= 15583856 |doi= 10.1007/s00018-004-4275-9 }}
* {{cite journal | vauthors = Iwahara T, Fujimoto J, Wen D, Cupples R, Bucay N, Arakawa T, Mori S, Ratzkin B, Yamamoto T | title = Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system | journal = Oncogene | volume = 14 | issue = 4 | pages = 439–49 | date = Jan 1997 | pmid = 9053841 | doi = 10.1038/sj.onc.1200849 }}
*{{cite journal | author=Morris SW, Kirstein MN, Valentine MB, ''et al.'' |title=Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. |journal=Science |volume=263 |issue= 5151 |pages= 1281-4 |year= 1994 |pmid= 8122112 |doi= }}
* {{cite journal | vauthors = Morris SW, Naeve C, Mathew P, James PL, Kirstein MN, Cui X, Witte DP | title = 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) | journal = Oncogene | volume = 14 | issue = 18 | pages = 2175–88 | date = May 1997 | pmid = 9174053 | doi = 10.1038/sj.onc.1201062 }}
*{{cite journal | author=Fujimoto J, Shiota M, Iwahara T, ''et al.'' |title=Characterization of the transforming activity of p80, a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t(2;5). |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=93 |issue= 9 |pages= 4181-6 |year= 1996 |pmid= 8633037 |doi= }}
* {{cite journal | vauthors = Bai RY, Dieter P, Peschel C, Morris SW, Duyster J | title = Nucleophosmin-anaplastic lymphoma kinase of large-cell anaplastic lymphoma is a constitutively active tyrosine kinase that utilizes phospholipase C-gamma to mediate its mitogenicity | journal = Molecular and Cellular Biology | volume = 18 | issue = 12 | pages = 6951–61 | date = Dec 1998 | pmid = 9819383 | pmc = 109278 | doi = 10.1128/mcb.18.12.6951}}
*{{cite journal | author=Iwahara T, Fujimoto J, Wen D, ''et al.'' |title=Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system. |journal=Oncogene |volume=14 |issue= 4 |pages= 439-49 |year= 1997 |pmid= 9053841 |doi= 10.1038/sj.onc.1200849 }}
* {{cite journal | vauthors = Hernández L, Pinyol M, Hernández S, Beà S, Pulford K, Rosenwald A, Lamant L, Falini B, Ott G, Mason DY, Delsol G, Campo E | title = TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma producing two structurally different TFG-ALK translocations | journal = Blood | volume = 94 | issue = 9 | pages = 3265–8 | date = Nov 1999 | pmid = 10556217 | doi =  }}
*{{cite journal | author=Morris SW, Naeve C, Mathew P, ''et al.'' |title=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) |journal=Oncogene |volume=14 |issue= 18 |pages= 2175-88 |year= 1997 |pmid= 9174053 |doi= 10.1038/sj.onc.1201062 }}
* {{cite journal | vauthors = Souttou B, Carvalho NB, Raulais D, Vigny M | title = Activation of anaplastic lymphoma kinase receptor tyrosine kinase induces neuronal differentiation through the mitogen-activated protein kinase pathway | journal = The Journal of Biological Chemistry | volume = 276 | issue = 12 | pages = 9526–31 | date = Mar 2001 | pmid = 11121404 | doi = 10.1074/jbc.M007333200 }}
*{{cite journal | author=Bai RY, Dieter P, Peschel C, ''et al.'' |title=Nucleophosmin-anaplastic lymphoma kinase of large-cell anaplastic lymphoma is a constitutively active tyrosine kinase that utilizes phospholipase C-gamma to mediate its mitogenicity. |journal=Mol. Cell. Biol. |volume=18 |issue= 12 |pages= 6951-61 |year= 1998 |pmid= 9819383 |doi=  }}
* {{cite journal | vauthors = Simonitsch I, Polgar D, Hajek M, Duchek P, Skrzypek B, Fassl S, Lamprecht A, Schmidt G, Krupitza G, Cerni C | title = The cytoplasmic truncated receptor tyrosine kinase ALK homodimer immortalizes and cooperates with ras in cellular transformation | journal = FASEB Journal | volume = 15 | issue = 8 | pages = 1416–8 | date = Jun 2001 | pmid = 11387242 | doi = 10.1096/fj.00-0678fje }}
*{{cite journal | author=Hernández L, Pinyol M, Hernández S, ''et al.'' |title=TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma producing two structurally different TFG-ALK translocations. |journal=Blood |volume=94 |issue= 9 |pages= 3265-8 |year= 1999 |pmid= 10556217 |doi= }}
* {{cite journal | vauthors = Zamo A, Chiarle R, Piva R, Howes J, Fan Y, Chilosi M, Levy DE, Inghirami G | title = Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death | journal = Oncogene | volume = 21 | issue = 7 | pages = 1038–47 | date = Feb 2002 | pmid = 11850821 | doi = 10.1038/sj.onc.1205152 }}
*{{cite journal | author=Souttou B, Carvalho NB, Raulais D, Vigny M |title=Activation of anaplastic lymphoma kinase receptor tyrosine kinase induces neuronal differentiation through the mitogen-activated protein kinase pathway. |journal=J. Biol. Chem. |volume=276 |issue= 12 |pages= 9526-31 |year= 2001 |pmid= 11121404 |doi= 10.1074/jbc.M007333200 }}
* {{cite journal | vauthors = Passoni L, Scardino A, Bertazzoli C, Gallo B, Coluccia AM, Lemonnier FA, Kosmatopoulos K, Gambacorti-Passerini C | title = ALK as a novel lymphoma-associated tumor antigen: identification of 2 HLA-A2.1-restricted CD8+ T-cell epitopes | journal = Blood | volume = 99 | issue = 6 | pages = 2100–6 | date = Mar 2002 | pmid = 11877285 | doi = 10.1182/blood.V99.6.2100 }}
*{{cite journal | author=Stoica GE, Kuo A, Aigner A, ''et al.'' |title=Identification of anaplastic lymphoma kinase as a receptor for the growth factor pleiotrophin. |journal=J. Biol. Chem. |volume=276 |issue= 20 |pages= 16772-9 |year= 2001 |pmid= 11278720 |doi= 10.1074/jbc.M010660200 }}
* {{cite journal | vauthors = Bonvini P, Gastaldi T, Falini B, Rosolen A | title = 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 | journal = Cancer Research | volume = 62 | issue = 5 | pages = 1559–66 | date = Mar 2002 | pmid = 11888936 | doi = }}
*{{cite journal | author=Simonitsch I, Polgar D, Hajek M, ''et al.'' |title=The cytoplasmic truncated receptor tyrosine kinase ALK homodimer immortalizes and cooperates with ras in cellular transformation. |journal=FASEB J. |volume=15 |issue= 8 |pages= 1416-8 |year= 2001 |pmid= 11387242 |doi= }}
* {{cite journal | vauthors = Hernández L, Beà S, Bellosillo B, Pinyol M, Falini B, Carbone A, Ott G, Rosenwald A, Fernández A, Pulford K, Mason D, Morris SW, Santos E, Campo E | title = 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 | journal = The American Journal of Pathology | volume = 160 | issue = 4 | pages = 1487–94 | date = Apr 2002 | pmid = 11943732 | pmc = 1867210 | doi = 10.1016/S0002-9440(10)62574-6 | displayauthors = 6 }}
*{{cite journal | author=Powers C, Aigner A, Stoica GE, ''et al.'' |title=Pleiotrophin signaling through anaplastic lymphoma kinase is rate-limiting for glioblastoma growth. |journal=J. Biol. Chem. |volume=277 |issue= 16 |pages= 14153-8 |year= 2002 |pmid= 11809760 |doi= 10.1074/jbc.M112354200 }}
* {{cite journal | vauthors = ten Berge RL, Meijer CJ, Dukers DF, Kummer JA, Bladergroen BA, Vos W, Hack CE, Ossenkoppele GJ, Oudejans JJ | title = Expression levels of apoptosis-related proteins predict clinical outcome in anaplastic large cell lymphoma | journal = Blood | volume = 99 | issue = 12 | pages = 4540–6 | date = Jun 2002 | pmid = 12036886 | doi = 10.1182/blood.V99.12.4540 }}
*{{cite journal  | author=Zamo A, Chiarle R, Piva R, ''et al.'' |title=Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death. |journal=Oncogene |volume=21 |issue= 7 |pages= 1038-47 |year= 2002 |pmid= 11850821 |doi= 10.1038/sj.onc.1205152 }}
* {{cite journal | vauthors = Dirks WG, Fähnrich S, Lis Y, Becker E, MacLeod RA, Drexler HG | title = Expression and functional analysis of the anaplastic lymphoma kinase (ALK) gene in tumor cell lines | journal = International Journal of Cancer | volume = 100 | issue = 1 | pages = 49–56 | date = Jul 2002 | pmid = 12115586 | doi = 10.1002/ijc.10435 }}
*{{cite journal | author=Passoni L, Scardino A, Bertazzoli C, ''et al.'' |title=ALK as a novel lymphoma-associated tumor antigen: identification of 2 HLA-A2.1-restricted CD8+ T-cell epitopes. |journal=Blood |volume=99 |issue= 6 |pages= 2100-6 |year= 2002 |pmid= 11877285 |doi=  }}
*{{cite journal | author=Bonvini P, Gastaldi T, Falini B, Rosolen A |title=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. |journal=Cancer Res. |volume=62 |issue= 5 |pages= 1559-66 |year= 2002 |pmid= 11888936 |doi=  }}
*{{cite journal  | author=Hernández L, Beà S, Bellosillo B, ''et al.'' |title=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. |journal=Am. J. Pathol. |volume=160 |issue= 4 |pages= 1487-94 |year= 2002 |pmid= 11943732 |doi=  }}
*{{cite journal  | author=ten Berge RL, Meijer CJ, Dukers DF, ''et al.'' |title=Expression levels of apoptosis-related proteins predict clinical outcome in anaplastic large cell lymphoma. |journal=Blood |volume=99 |issue= 12 |pages= 4540-6 |year= 2002 |pmid= 12036886 |doi=  }}
*{{cite journal  | author=Cools J, Wlodarska I, Somers R, ''et al.'' |title=Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor. |journal=Genes Chromosomes Cancer |volume=34 |issue= 4 |pages= 354-62 |year= 2002 |pmid= 12112524 |doi= 10.1002/gcc.10033 }}
*{{cite journal | author=Dirks WG, Fähnrich S, Lis Y, ''et al.'' |title=Expression and functional analysis of the anaplastic lymphoma kinase (ALK) gene in tumor cell lines. |journal=Int. J. Cancer |volume=100 |issue= 1 |pages= 49-56 |year= 2002 |pmid= 12115586 |doi= 10.1002/ijc.10435 }}
}}
{{refend}}
{{refend}}


==External links==
== External links ==
* {{MeshName|ALK+protein,+human}}
* {{MeshName|ALK+protein,+human}}
*[http://www.nextbio.com/b/home/home.nb?q=ALK ALK Correlations, Experiments, Publications and Clinical Trials]
* [https://www.ncbi.nlm.nih.gov/books/NBK24599/  GeneReviews/NCBI/NIH/UW entry on ALK-Related Neuroblastoma Susceptibility]
* [https://www.ncbi.nlm.nih.gov/omim/105590,256700,105590,256700  OMIM entries on ALK-Related Neuroblastoma Susceptibility]
* {{UCSC gene info|ALK}}


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{{Clusters of differentiation}}
{{Tyrosine kinases}}
{{Enzymes}}
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[[Category:Clusters of differentiation]]
[[Category:Clusters of differentiation]]
[[Category:Tyrosine kinase receptors]]

Latest revision as of 19:58, 30 August 2018

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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]

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.[3] 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.[4]

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.[citation needed] Other techniques like reverse-transcriptase PCR (RT-PCR) can also be used to detect lung cancers with an ALK gene fusion but not recommended.[citation needed] 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.[5]

Gene rearrangements and overexpression in other tumours

ALK inhibitors

Main article: ALK inhibitor
  • Xalkori (crizotinib), produced by Pfizer, was approved by the FDA for treatment of late stage lung cancer on August 26, 2011.[20] 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.[21]
  • 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

References

  1. ↑ 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.
  2. ↑ 2.0 2.1 "Entrez Gene: ALK anaplastic lymphoma kinase (Ki-1)".
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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. doi:10.3748/wjg.v12.i44.7104. PMID 17131471.
  14. ↑ 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.
  15. ↑ 15.0 15.1 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ "Xalkori Approved for Lung Cancer". FDA.
  21. ↑ "ZYKADIA (ceritinib) capsules, for oral use Initial U.S. Approval: 2014" (PDF). United States Food and Drug Administration.

Further reading

External links

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

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