Anaplastic lymphoma kinase

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Available structures
PDBOrtholog search: PDBe RCSB
AliasesALK, CD246, NBLST3, Anaplastic lymphoma kinase, anaplastic lymphoma receptor tyrosine kinase, ALK receptor tyrosine kinase
External IDsOMIM: 105590 MGI: 103305 HomoloGene: 68387 GeneCards: ALK
Gene location (Human)
Chromosome 2 (human)
Chr.Chromosome 2 (human)[1]
Chromosome 2 (human)
Genomic location for ALK
Genomic location for ALK
Band2p23.2-p23.1Start29,192,774 bp[1]
End29,921,586 bp[1]
RNA expression pattern
PBB GE ALK 208212 s at fs.png

PBB GE ALK 208211 s at fs.png
More reference expression data
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 2: 29.19 – 29.92 MbChr 17: 71.87 – 72.6 Mb
PubMed search[3][4]
View/Edit HumanView/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.[5][6]


Anaplastic lymphoma kinase (ALK) was originally discovered in 1994[5][7] in anaplastic large-cell lymphoma (ALCL, from which ALK was named) resulting from a translocation event between chromosomes (2;5)(p23:q35). This translocation generates a fusion protein, NPM-ALK, in which the kinase domain of ALK is fused to a part of the nucleophosmin (NPM) protein, which dimerizes and thus constitutively activates the ALK kinase domain.

The full-length protein ALK was then identified in 1997 simultaneously by two groups.[8][9] The deduced amino acid sequences revealed that ALK was a novel receptor tyrosine kinase (RTK), having an extracellular ligand-binding domain, a transmembrane domain and an intracellular tyrosine kinase domain.[8][9] While the tyrosine kinase domain of human ALK shares a high degree of similarity with that of the insulin receptor (IR), its extracellular domain is unique among the RTK family and contains two MAM domains (meprin, A5 protein and receptor protein tyrosine phosphatase mu), a LDLa domain (low-density lipoprotein receptor class A) and a glycine-rich region.[9][10] Based on overall homology, ALK is highly related to the leucocyte receptor tyrosine kinase (LTK) and, together with the insulin receptor, they form a subgroup in the RTK superfamily.[8][9] The human ALK gene encodes a protein of 180 kDa composed of 1620 amino acids.[8][9]

Following the original discovery of the receptor in mammals, several orthologs of ALK have been identified in the fruit fly Drosophila melanogaster (dAlk) in 2001,[10] in the nematode Caenorhabditis elegans (scd-2) in 2004[11] and in the zebrafish Danio rerio (DrAlk) in 2013.[12]

The ligands of the human ALK/LTK receptors have been identified more recently, in 2014:[13][14][15] FAM150A (AUGβ) and FAM150B (AUGα), two small secreted peptides that strongly activate ALK signaling. The ligands are in Drosophila, Jelly belly (Jeb),[16][17] and in C. elegans, HEN-1.[18] No such ligand has been reported yet in zebrafish or in other vertebrates.


As the majority of RTKs, following binding of the ligand, the full-length receptor ALK dimerizes, changes conformation and auto-activates its own kinase domain, which in turn phosphorylates in trans other ALK receptors on specific tyrosine amino acid residues. ALK phosphorylated residues serve as binding sites for the recruitment of several adaptor and other cellular proteins, such as GRB2,[19] IRS1,[19][20] Shc,[19][21] Src,[22] FRS2,[21] PTPN11/Shp2,[23] PLCγ,[24][20] PI3K,[25][20] and NF1.[26] Other reported downstream ALK targets include FOXO3a,[27] CDKN1B/p27kip,[28] cyclin D2, NIPA,[29][30] RAC1,[31] CDC42,[32] p130CAS,[33] SHP1,[34] and PIKFYVE.[35]

Phosphorylated ALK activates multiple downstream signal transduction pathways, such as the MAPK-ERK, the PI3K-AKT, the PLCγ, the CRKL-C3G, and the JAK-STAT pathways among other.[36][37]


The receptor ALK plays a pivotal role in cellular communication and in the normal development and function of the nervous system.[6] This observation is based on the extensive expression of ALK messenger RNA (mRNA) throughout the nervous system during mouse embryogenesis.[8][9][38] In agreement with this observation, many in vitro functional studies demonstrated that ALK activation promotes neuronal differentiation of PC12[39][40][41][21] or neuroblastoma cell lines.[20]

ALK is critical for embryonic development in Drosophila, as flies lacking the receptor die due to the lack of specification of a particular cell type, the founder cell, in the embryonic visceral muscle.[16][17][42] However, in ALK knockout mice, while defects in neurogenesis and testosterone production have been reported, these mice are viable, suggesting that ALK is not critical to developmental processes.[43][44][45]

ALK plays his most important roles in the functioning of the nervous system: in retinal axon targeting in the visual system,[46] in the regulation of growth/size of the whole organism,[26] in organ growth,[47] and in the development of the synapses[11] at the neuromuscular junction.[48][49] ALK also plays crucial roles in adult behavior, as it regulates behavioral responses to ethanol[50][51][52][53] and sleep,[54] and it restricts and constrains learning and long-term memory.[26][55][44]


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.[36][37]

Anaplastic large-cell lymphoma[edit]

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.[56]

Adenocarcinoma of the lung[edit]

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.[57]

Gene rearrangements and overexpression in other tumours[edit]

ALK inhibitors[edit]

  • Xalkori (crizotinib), produced by Pfizer, was approved by the FDA for treatment of late stage lung cancer on August 26, 2011.[72] 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.[73]
  • 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[edit]


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Further reading[edit]

  • Benharroch D, Meguerian-Bedoyan Z, Lamant L, Amin C, Brugières L, Terrier-Lacombe MJ, et al. (March 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, et al. (December 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.
  • Hernández L, Pinyol M, Hernández S, Beà S, Pulford K, Rosenwald A, et al. (November 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.
  • Simonitsch I, Polgar D, Hajek M, Duchek P, Skrzypek B, Fassl S, et al. (June 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, et al. (February 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, et al. (March 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 (March 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. (April 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, et al. (June 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 (July 2002). "Expression and functional analysis of the anaplastic lymphoma kinase (ALK) gene in tumor cell lines". International Journal of Cancer. 100 (1): 49–56. doi:10.1002/ijc.10435. PMID 12115586.

External links[edit]

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