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Details on Person UniProt:Q9UM73 ALK
| Class:Id | ReferenceGeneProduct:49894 |
|---|---|
| _chainChangeLog | signal peptide:1-18 added on Sat February 7 2015;chain:19-1620 added on Sat February 7 2015 |
| _displayName | UniProt:Q9UM73 ALK |
| _timestamp | 2026-02-20 22:29:35 |
| chain | signal peptide:1-18 chain:19-1620 |
| checksum | 0733D6C4FD212F41 |
| comment | FUNCTION Neuronal receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system (PubMed:11121404, PubMed:11387242, PubMed:16317043, PubMed:17274988, PubMed:30061385, PubMed:34646012, PubMed:34819673). Also acts as a key thinness protein involved in the resistance to weight gain: in hypothalamic neurons, controls energy expenditure acting as a negative regulator of white adipose tissue lipolysis and sympathetic tone to fine-tune energy homeostasis (By similarity). Following activation by ALKAL2 ligand at the cell surface, transduces an extracellular signal into an intracellular response (PubMed:30061385, PubMed:33411331, PubMed:34646012, PubMed:34819673). In contrast, ALKAL1 is not a potent physiological ligand for ALK (PubMed:34646012). Ligand-binding to the extracellular domain induces tyrosine kinase activation, leading to activation of the mitogen-activated protein kinase (MAPK) pathway (PubMed:34819673). Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif (PubMed:15226403, PubMed:16878150). Induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1 (PubMed:15226403, PubMed:16878150). ALK activation may also be regulated by pleiotrophin (PTN) and midkine (MDK) (PubMed:11278720, PubMed:11809760, PubMed:12107166, PubMed:12122009). PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation (PubMed:11278720, PubMed:11809760, PubMed:12107166). MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction (PubMed:12122009). Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase (PubMed:15226403, PubMed:16878150). Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK (PubMed:15226403, PubMed:16878150). May function as regulator of gastric epithelial differentiation (By similarity).CATALYTIC ACTIVITY L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+)ACTIVITY REGULATION Activated upon ALKAL2 ligand-binding (PubMed:34646012, PubMed:34819673). ALKAL2-driven activation is coupled with heparin-binding (PubMed:25605972, PubMed:34646012). Following ligand-binding, homodimerizes and autophosphorylates, activating its kinase activity (PubMed:16317043, PubMed:17681947, PubMed:34646012, PubMed:34819673). Inactivated through dephosphorylation by receptor protein tyrosine phosphatase beta and zeta complex (PTPRB/PTPRZ1) when there is no stimulation by a ligand (PubMed:17681947). Staurosporine, crizotinib and CH5424802 act as inhibitors of ALK kinase activity (PubMed:21575866).SUBUNIT Homodimer; homodimerizes following heparin- and ligand-binding (PubMed:16317043, PubMed:25605972, PubMed:34646012, PubMed:34819673). Interacts with CBL, IRS1, PIK3R1 and PLCG1 (PubMed:15226403). Interacts with FRS2 and SHC1 (PubMed:15226403, PubMed:16878150, PubMed:17274988). Interacts with PTN and MDK (PubMed:11278720, PubMed:12122009).INTERACTION Membrane attachment is essential for promotion of neuron-like differentiation and cell proliferation arrest through specific activation of the MAP kinase pathway.TISSUE SPECIFICITY Expressed in brain and CNS. Also expressed in the small intestine and testis, but not in normal lymphoid cells.DOMAIN The EGF-like region drives the cytokine specificity for ALKAL2.DOMAIN The heparin-binding region binds heparin glycosaminoglycan (PubMed:25605972, PubMed:34646012). Heparin-binding is required for ALKAL2-driven activation (PubMed:34646012).PTM Phosphorylated at tyrosine residues by autocatalysis, which activates kinase activity (PubMed:11121404, PubMed:15938644, PubMed:16878150, PubMed:34819673). In cells not stimulated by a ligand, receptor protein tyrosine phosphatase beta and zeta complex (PTPRB/PTPRZ1) dephosphorylates ALK at the sites in ALK that are undergoing autophosphorylation through autoactivation (PubMed:17681947). Phosphorylation at Tyr-1507 is critical for SHC1 association (PubMed:17274988).PTM N-glycosylated.DISEASE A chromosomal aberration involving ALK is found in a form of non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) with NPM1. The resulting chimeric NPM1-ALK protein homodimerize and the kinase becomes constitutively activated. The constitutively active fusion proteins are responsible for 5-10% of non-Hodgkin lymphomas.DISEASE A chromosomal aberration involving ALK is associated with inflammatory myofibroblastic tumors (IMTs). Translocation t(2;11)(p23;p15) with CARS; translocation t(2;4)(p23;q21) with SEC31A.DISEASE A chromosomal aberration involving ALK is associated with anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25) with ALO17.DISEASE Disease susceptibility is associated with variants affecting the gene represented in this entry.DISEASE The ALK signaling pathway plays an important role in glioblastoma, the most common malignant brain tumor of adults and one of the most lethal cancers. It regulates both glioblastoma migration and growth.DISEASE A chromosomal aberration involving ALK is found in one subject with colorectal cancer. Translocation t(2;2)(p23.1;p23.3). A 5 million base pair tandem duplication generates an in-frame WDCP-ALK gene fusion.DISEASE A chromosomal aberration involving ALK has been identified in a subset of patients with non-small-cell lung carcinoma. This aberration leads to the production of a fusion protein between the N-terminus of EML4 et the C-terminus of ALK. It is unclear whether the fusion protein is caused by a simple inversion within 2p (inv(2)(p21p23)) or whether the chromosome translocation involving 2p is more complex. When tested in a heterologous system, the fusion protein EML4-ALK possesses transforming activity that is dependent on ALK catalytic activity, possibly due to spontaneous dimerization mediated by the EML4 moiety, leading to ALK kinase activation.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. Insulin receptor subfamily.SEQUENCE CAUTION Extended N-terminus. |
| description | recommendedName: fullName evidence="42"ALK tyrosine kinase receptor ecNumber evidence="33 36"2.7.10.1 alternativeName: fullName evidence="41"Anaplastic lymphoma kinase cdAntigenNameCD246/cdAntigenName |
| geneName | ALK |
| identifier | Q9UM73 |
| isSequenceChanged | FALSE |
| keyword | 3D-structure ATP-binding Cell membrane Chromosomal rearrangement Disease variant Disulfide bond Glycoprotein Kinase Membrane Nucleotide-binding Phosphoprotein Proteomics identification Proto-oncogene Receptor Reference proteome Repeat Signal Transferase Transmembrane Transmembrane helix Tyrosine-protein kinase |
| modified | [InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9939033] Weiser, Joel, 2025-02-21 [InstanceEdit:9983091] Weiser, Joel, 2026-02-20 |
| name | ALK |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| referenceGene | [ReferenceDNASequence:8999903] ENSEMBL:ENSG00000171094 ALK [Homo sapiens] |
| secondaryIdentifier | ALK_HUMAN A6P4T4 A6P4V4 Q4ZFX9 Q53QQ6 Q53RZ4 Q59FI3 Q9Y4K6 |
| sequenceLength | 1620 |
| species | [Species:48887] Homo sapiens |
| (referenceEntity) | [EntityWithAccessionedSequence:201502] ALK [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:201535] p-7Y-ALK [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:9699794] ALK F1174I [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:9699797] ALK G1128V [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:9699800] p-7Y ALK R1275L [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:9699801] ALK F1174L [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:9699802] ALK R1192P [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:9699805] ALK F1245L [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:9699811] ALK F1245C [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:9699818] ALK F1174V [plasma membrane] [Homo sapiens] |
| (referenceSequence) | [ModifiedResidue:201491] O4'-phospho-L-tyrosine at 567 [ModifiedResidue:201503] O4'-phospho-L-tyrosine at 156 [ModifiedResidue:201525] O4'-phospho-L-tyrosine at 664 [ModifiedResidue:9699796] O4'-phospho-L-tyrosine at 1096 [ModifiedResidue:9699803] O4'-phospho-L-tyrosine at 1604 [FragmentInsertionModification:9699804] Insertion of residues 1058 to 1620 at 118 from UniProt:Q9UM73 ALK [ReplacedResidue:9699808] L-phenylalanine 1245 replaced with L-valine [ReplacedResidue:9699810] L-phenylalanine 1174 replaced with L-isoleucine [ReplacedResidue:9699814] L-isoleucine 1171 replaced with L-threonine [ReplacedResidue:9699815] L-threonine 1151 replaced with L-methionine |
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No pathways have been reviewed or authored by UniProt:Q9UM73 ALK (49894)
