Protein-coding gene in the species Homo sapiens
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 receptor tyrosine kinase, ALK receptor tyrosine kinase, ALK (gene), ALK1External IDs
OMIM :
105590
MGI :
103305
HomoloGene :
68387
GeneCards :
ALK
RNA expression pattern
Bgee
Human
Mouse (ortholog)
Top expressed in sperm ventral tegmental area superior vestibular nucleus internal globus pallidus subthalamic nucleus Brodmann area 23 inferior ganglion of vagus nerve middle temporal gyrus trigeminal ganglion spinal ganglia
Top expressed in inferior ganglion of vagus nerve endolymphatic sac external carotid artery Jacobson's organ entorhinal cortex optic chiasm posterior semicircular canal sublingual gland inferior olivary nucleus Greater petrosal nerve
More reference expression data
BioGPS
Wikidata
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]
Identification
Anaplastic lymphoma kinase (ALK) was originally discovered in 1994
[5]
[7] in
anaplastic large-cell lymphoma (ALCL) cells. ALCL is caused by a (2;5)(p23:q35)
chromosomal translocation that generates the
fusion protein NPM-ALK, in which the
kinase domain of ALK is fused to the amino-terminal part of the
nucleophosmin (NPM) protein.
Dimerization of NPM constitutively activates the ALK kinase domain.
[5]
[7]
The full-length protein ALK was identified in 1997 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 , its extracellular domain is unique among the RTK family in containing two
MAM domains (
meprin , A5 protein and
receptor protein
tyrosine phosphatase mu), an LDLa domain (
low-density lipoprotein receptor class A) and a
glycine -rich region.
[9]
[10] Based on overall homology, ALK is closely related to the
leukocyte receptor tyrosine kinase (LTK) and, together with the insulin receptor, forms a subgroup in the RTK superfamily.
[8]
[9] The human ALK gene encodes a protein 1,620 amino acids long with a
molecular weight of 180
kDa .
[8]
[9]
Since the original discovery of the receptor in mammals, several
orthologs of ALK have been identified: dAlk in the
fruit fly (
Drosophila melanogaster ) in 2001,
[10] scd-2 in the
nematode (
Caenorhabditis elegans ) in 2004,
[11] and DrAlk in the
zebrafish (
Danio rerio ) in 2013.
[12]
The
ligands of the human ALK/LTK receptors were identified in 2014:
[13]
[14]
[15] FAM150A (AUGβ) and FAM150B (AUGα), two small secreted
peptides that strongly activate ALK signaling. In invertebrates, ALK-activating ligands are Jelly belly (Jeb) in Drosophila ,
[16]
[17] and hesitation behaviour 1 (HEN-1) in C. elegans .
[18] No such ligands have been reported yet in zebrafish or other
vertebrates .
[19]
Mechanism
Following binding of the ligand, the full-length receptor ALK
dimerizes ,
changes conformation , and
autoactivates its own
kinase domain, which in turn
phosphorylates other ALK receptors
in trans 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 ,
[20]
IRS1 ,
[20]
[21]
Shc ,
[20]
[22]
Src ,
[23]
FRS2 ,
[22]
PTPN11/Shp2 ,
[24]
PLCγ ,
[25]
[21]
PI3K ,
[26]
[21] and
NF1 .
[27] Other reported downstream ALK targets include
FOXO3a ,
[28]
CDKN1B/p27kip ,
[29]
cyclin D2 ,
NIPA ,
[30]
[31]
RAC1 ,
[32]
CDC42 ,
[33] p130CAS,
[34]
SHP1 ,
[35] and
PIKFYVE .
[36]
Phosphorylated ALK activates multiple downstream
signal transduction pathways, including
MAPK-ERK ,
PI3K-AKT ,
PLCγ ,
CRKL-C3G , and
JAK-STAT .
[37]
[19]
Function
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 vitro functional studies have demonstrated that ALK activation promotes
neuronal
differentiation of
PC12
[39]
[40]
[41]
[22] or
neuroblastoma cell lines.
[21]
ALK is critical for
embryonic development in
Drosophila . Flies lacking the receptor die due to failure of founder cell specification in embryonic visceral muscle.
[16]
[17]
[42] However, while ALK
knockout mice exhibit defects in
neurogenesis and
testosterone production, they remain viable, suggesting that ALK is not critical to their developmental processes.
[43]
[44]
[45]
ALK regulates
retinal
axon targeting ,
[46] growth and size,
[27]
[47]
synapse development
[11] at the
neuromuscular junction ,
[48]
[49] behavioral responses to
ethanol ,
[50]
[51]
[52]
[53] and
sleep .
[54] It restricts and constrains
learning and
long-term memory
[27]
[55]
[44] and
small-molecule inhibitors of the ALK receptor can improve learning,
[27] long-term memory,
[55] and extend healthy
lifespan .
[56] ALK is also a candidate
thinness gene, as its genetic deletion leads to resistance to diet- and
leptin -mutation-induced
obesity .
[57]
[N 1]
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.
[37]
[19]
Anaplastic large-cell lymphoma
The 2;5 chromosomal translocation is associated with approximately 60% of
anaplastic large-cell lymphomas (ALCLs), type
ALK-positive anaplastic large cell lymphoma and very rare cases of ALCL type
primary cutaneous anaplastic large cell lymphoma . 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 .
[58]
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.
[59] Patients with this ALK rearrangement have the following clinicopathologic characteristics: Young age at diagnosis (median 50 years), female gender, nonsmoker/light smoker, adenocarcinoma histology with specific morphologic patterns such as cribriform and solid signet ring, expression of thyroid transcription factor 1, tendency to metastasize to pleura or pericardium, frequently with more metastases than other molecular types, and predominantly metastases to the central nervous system.
[60] 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.
[59] 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.
[61]
Gene rearrangements and overexpression in other tumours
ALK inhibitors
Xalkori (
crizotinib ), produced by Pfizer, was approved by the FDA for treatment of late stage lung cancer on August 26, 2011.
[76] 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%.
In patients affected by relapsed or refractory ALK+ Anaplastic Large Cell Lymphoma, crizotinib produced objective response rates ranging from 65% to 90% and 3 year progression free survival rates of 60-75%. No relapse of the lymphoma was ever observed after the initial 100 days of treatment. Treatment must be continued indefinitely at present.
[77]
[78]
[79]
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.
[80]
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
Notes and references
Notes
^ In 2020, a genome-wide association study (GWAS) was published of 47,102 people in the Estonian Genome Center of the University of Tartu (EGCUT) Biobank which compared the DNA of healthy thin individuals in the lowest 6th percentile of body mass index to the DNA of normal-weight individuals. This study identified a number of genetic variations of the ALK gene that were associated with thinness. As a next step, experiments in mice and Drosophila fruit flies showed that mice in which the ALK gene was knocked out had the similar activity and diet levels as normal mice, but had lower body fat and weight from early age into adulthood. This implies that inhibition of this kinase, already of interest as a chemotherapy for cancers associated with this gene, might be a way to prevent weight gain.
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Further reading
Benharroch D, Meguerian-Bedoyan Z, Lamant L, Amin C, Brugières L, Terrier-Lacombe MJ, et al. (March 1998).
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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): 2939–2953.
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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): 3265–3268.
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Simonitsch I, Polgar D, Hajek M, Duchek P, Skrzypek B, Fassl S, et al. (June 2001).
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Zamo A, Chiarle R, Piva R, Howes J, Fan Y, Chilosi M, et al. (February 2002).
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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): 2100–2106.
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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): 1559–1566.
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Hernández L, Beà S, Bellosillo B, Pinyol M, Falini B, Carbone A, et al. (April 2002).
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ten Berge RL, Meijer CJ, Dukers DF, Kummer JA, Bladergroen BA, Vos W, et al. (June 2002).
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Dirks WG, Fähnrich S, Lis Y, Becker E, MacLeod RA, Drexler HG (July 2002).
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External links
This article incorporates text from the
United States National Library of Medicine , which is in the
public domain .
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Activity Regulation Classification Kinetics Types