P0DV84 · ALK_CANLF
- ProteinALK tyrosine kinase receptor
- GeneALK
- StatusUniProtKB reviewed (Swiss-Prot)
- Amino acids1631 (go to sequence)
- Protein existenceInferred from homology
- Annotation score5/5
Function
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 (By similarity).
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. In contrast, ALKAL1 is not a potent physiological ligand for ALK. Ligand-binding to the extracellular domain induces tyrosine kinase activation, leading to activation of the mitogen-activated protein kinase (MAPK) pathway. Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif. Induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. ALK activation may also be regulated by pleiotrophin (PTN) and midkine (MDK). PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation. 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. Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase. Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK (By similarity).
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. In contrast, ALKAL1 is not a potent physiological ligand for ALK. Ligand-binding to the extracellular domain induces tyrosine kinase activation, leading to activation of the mitogen-activated protein kinase (MAPK) pathway. Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif. Induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. ALK activation may also be regulated by pleiotrophin (PTN) and midkine (MDK). PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation. 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. Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase. Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK (By similarity).
Catalytic activity
- ATP + L-tyrosyl-[protein] = ADP + H+ + O-phospho-L-tyrosyl-[protein]
Activity regulation
Activated upon ALKAL2 ligand-binding (By similarity).
ALKAL2-driven activation is coupled with heparin-binding (PubMed:25605972).
Following ligand-binding, homodimerizes and autophosphorylates, activating its kinase activity (By similarity).
Inactivated through dephosphorylation by receptor protein tyrosine phosphatase beta and zeta complex (PTPRB/PTPRZ1) when there is no stimulation by a ligand (By similarity).
ALKAL2-driven activation is coupled with heparin-binding (PubMed:25605972).
Following ligand-binding, homodimerizes and autophosphorylates, activating its kinase activity (By similarity).
Inactivated through dephosphorylation by receptor protein tyrosine phosphatase beta and zeta complex (PTPRB/PTPRZ1) when there is no stimulation by a ligand (By similarity).
Features
Showing features for binding site, active site.
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | plasma membrane | |
Cellular Component | receptor complex | |
Molecular Function | ATP binding | |
Molecular Function | transmembrane receptor protein tyrosine kinase activity | |
Biological Process | cell surface receptor protein tyrosine kinase signaling pathway | |
Biological Process | regulation of cell population proliferation | |
Biological Process | regulation of neuron differentiation |
Keywords
- Molecular function
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameALK tyrosine kinase receptor
- EC number
Gene names
Organism names
- Strain
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Laurasiatheria > Carnivora > Caniformia > Canidae > Canis
Accessions
- Primary accessionP0DV84
Proteomes
Subcellular Location
UniProt Annotation
GO Annotation
Cell membrane ; Single-pass type I membrane protein
Note: Membrane attachment is essential for promotion of neuron-like differentiation and cell proliferation arrest through specific activation of the MAP kinase pathway.
Features
Showing features for topological domain, transmembrane.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Topological domain | 19-1053 | Extracellular | ||||
Sequence: SGSGAGTGSGTGSGTGTGTGQLVGSPATGPALQPREPLSYSRLQRKSLAVDFVVPSLFRVYARDLLLPPWSSSEPRAGWTEARGSLALDCAPLLRLLGPPPGVSWAEGASSPAPAQARTLTRVLKGGSVRKLRRAKQLVLELGEEAILEGCVGPSPEEVTAGLLQFNLSELFSWWIRHGEGRLRIRLMPEKKASAVGREGRLSAAIRASQPRLLFQILGTGHSSLESPTSLPSPPPDPFAWNLTWIMKDSFPFLSHRSRYGLECSFDFPCELEYSPPLHDLGNQSWSWRRVPSEEASQMDLLDGPETEHSKEMPRGSFLLLNTSANSKHTILSPWMRSSSEHCKLAVSVHRHLQPSGRYVAQLLPHNEPGREILLVPTPGKHGWTVLQGRIGRPENPFRVALEYISSGNRSLSAVDFFALKNCSEGTSPGSKMALQSSFTCWNGTVLQLGQACDFHQDCAQGEDEGQLCSQLPAGFYCNFENGFCGWSQGILTPHNPRWQVRTLKDARVQDHRGHALSLSTTDVPTSESATVTSATFPAPMKNSPCELRMSWLIHGVLRGNVSLVLVENKTGKEQSRMVWHVATNEGLSLWQWTVLPLLDVADRFWLQIVAWWGQGSRATVAFDNISISLDCYLTISGEEKMLQNTAPKSRNLFERNPNKDPRPWENTRETPVFDPTVHWLFTTCGASGPHGPTQAQCNNAYRNSNLSVVVGSEGPLKGIQTWKVPATDTYSISGYGAAGGKGGKNTMMRSHGVSVLGIFNLEKGDTLYILVGQQGEDACPSTNRLIQKVCIGENNVIEEEIRVNRSVHEWAGGGGGGGGATYVFKMKDGVPVPLIIAAGGGGRAYGAKTDTFHPERLENNSSVLGLNGNSGAAGGGGGWNDNTSLLWSGKSLLEGATGGHSCPQAMKKWGWETRGGFGGGGGGCSSGGGGGGYIGGNAASNNDPEMDGEDGVSFISPLGILYTPALKVMEGHGEVNIKHYLNCSHCEGDECHMDPESHKVICFCDHGTVLAEDGVSCIVSPTPEPHLPLSLVLS | ||||||
Transmembrane | 1054-1074 | Helical | ||||
Sequence: VVTSALVAALVLAFSGIMIVY | ||||||
Topological domain | 1075-1631 | Cytoplasmic | ||||
Sequence: RRKHQELQAMQMELQSPEYKLSKLRTSTIMTDYNPNYCFAGKTSSISDLKEVPRKNITLIRGLGHGAFGEVYEGQVSGVPSDPSPLQVAVKTLPEVCSEQDELDFLMEALIISKFNHQNIVRCIGVSLQALPRFILLELMAGGDLKSFLRETRPRPNQPSSLAMLDLLHVAQDIACGCQYLEENHFIHRDIAARNCLLTCPGPGRVAKIGDFGMARDIYRASYYRKGGCAMLPVKWMPPEAFMEGIFTSKTDTWSFGVLLWEIFSLGYMPYPSKSNQEVLEFVTSGGRMDPPKNCPGPVYRIMTQCWQHQPEDRPNFAIILERIEYCTQDPDVINTALPVEYGPLMEEEEKVPMRPQDPEGIPPLLVSPPQAKREEGPDPAAPPPLPSTSSGKAAKKPTAAELSGRVTRGPAVEGGHVNMAFSQSNPASELHKVQGSRNKPTSLWNPTYGSWFTEKPTKKNNPPATKGHHDRGNLGREGSCTVPPNVAAGRLPGASLLLEPSSLTASMKEVPLFRLRHFPCGNVNYGYQQQGLPFEGTTAPGSSQYEDALLKTPPGP |
Keywords
- Cellular component
PTM/Processing
Features
Showing features for signal, chain, glycosylation, disulfide bond.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Signal | 1-18 | |||||
Sequence: MGSVGLLGLLLLRLSVTA | ||||||
Chain | PRO_5023874220 | 19-1631 | ALK tyrosine kinase receptor | |||
Sequence: SGSGAGTGSGTGSGTGTGTGQLVGSPATGPALQPREPLSYSRLQRKSLAVDFVVPSLFRVYARDLLLPPWSSSEPRAGWTEARGSLALDCAPLLRLLGPPPGVSWAEGASSPAPAQARTLTRVLKGGSVRKLRRAKQLVLELGEEAILEGCVGPSPEEVTAGLLQFNLSELFSWWIRHGEGRLRIRLMPEKKASAVGREGRLSAAIRASQPRLLFQILGTGHSSLESPTSLPSPPPDPFAWNLTWIMKDSFPFLSHRSRYGLECSFDFPCELEYSPPLHDLGNQSWSWRRVPSEEASQMDLLDGPETEHSKEMPRGSFLLLNTSANSKHTILSPWMRSSSEHCKLAVSVHRHLQPSGRYVAQLLPHNEPGREILLVPTPGKHGWTVLQGRIGRPENPFRVALEYISSGNRSLSAVDFFALKNCSEGTSPGSKMALQSSFTCWNGTVLQLGQACDFHQDCAQGEDEGQLCSQLPAGFYCNFENGFCGWSQGILTPHNPRWQVRTLKDARVQDHRGHALSLSTTDVPTSESATVTSATFPAPMKNSPCELRMSWLIHGVLRGNVSLVLVENKTGKEQSRMVWHVATNEGLSLWQWTVLPLLDVADRFWLQIVAWWGQGSRATVAFDNISISLDCYLTISGEEKMLQNTAPKSRNLFERNPNKDPRPWENTRETPVFDPTVHWLFTTCGASGPHGPTQAQCNNAYRNSNLSVVVGSEGPLKGIQTWKVPATDTYSISGYGAAGGKGGKNTMMRSHGVSVLGIFNLEKGDTLYILVGQQGEDACPSTNRLIQKVCIGENNVIEEEIRVNRSVHEWAGGGGGGGGATYVFKMKDGVPVPLIIAAGGGGRAYGAKTDTFHPERLENNSSVLGLNGNSGAAGGGGGWNDNTSLLWSGKSLLEGATGGHSCPQAMKKWGWETRGGFGGGGGGCSSGGGGGGYIGGNAASNNDPEMDGEDGVSFISPLGILYTPALKVMEGHGEVNIKHYLNCSHCEGDECHMDPESHKVICFCDHGTVLAEDGVSCIVSPTPEPHLPLSLVLSVVTSALVAALVLAFSGIMIVYRRKHQELQAMQMELQSPEYKLSKLRTSTIMTDYNPNYCFAGKTSSISDLKEVPRKNITLIRGLGHGAFGEVYEGQVSGVPSDPSPLQVAVKTLPEVCSEQDELDFLMEALIISKFNHQNIVRCIGVSLQALPRFILLELMAGGDLKSFLRETRPRPNQPSSLAMLDLLHVAQDIACGCQYLEENHFIHRDIAARNCLLTCPGPGRVAKIGDFGMARDIYRASYYRKGGCAMLPVKWMPPEAFMEGIFTSKTDTWSFGVLLWEIFSLGYMPYPSKSNQEVLEFVTSGGRMDPPKNCPGPVYRIMTQCWQHQPEDRPNFAIILERIEYCTQDPDVINTALPVEYGPLMEEEEKVPMRPQDPEGIPPLLVSPPQAKREEGPDPAAPPPLPSTSSGKAAKKPTAAELSGRVTRGPAVEGGHVNMAFSQSNPASELHKVQGSRNKPTSLWNPTYGSWFTEKPTKKNNPPATKGHHDRGNLGREGSCTVPPNVAAGRLPGASLLLEPSSLTASMKEVPLFRLRHFPCGNVNYGYQQQGLPFEGTTAPGSSQYEDALLKTPPGP | ||||||
Glycosylation | 185 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 260 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 301 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 340 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 427 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 440 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 461 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 579 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 587 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 643 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Disulfide bond | 703↔716 | |||||
Sequence: CGASGPHGPTQAQC | ||||||
Glycosylation | 724 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Disulfide bond | 798↔809 | |||||
Sequence: CPSTNRLIQKVC | ||||||
Glycosylation | 823 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 878 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 879 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 901 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Disulfide bond | 921↔943 | |||||
Sequence: CPQAMKKWGWETRGGFGGGGGGC | ||||||
Glycosylation | 1001 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Disulfide bond | 1002↔1010 | |||||
Sequence: CSHCEGDEC | ||||||
Disulfide bond | 1005↔1021 | |||||
Sequence: CEGDECHMDPESHKVIC | ||||||
Disulfide bond | 1023↔1036 | |||||
Sequence: CDHGTVLAEDGVSC |
Post-translational modification
Phosphorylated at tyrosine residues by autocatalysis, which activates kinase activity. 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.
Keywords
- PTM
PTM databases
Interaction
Subunit
Homodimer; homodimerizes following heparin- and ligand-binding (PubMed:25605972).
Interacts with CBL, IRS1, PIK3R1 and PLCG1. Interacts with FRS2 and SHC1. Interacts with PTN and MDK (By similarity).
Interacts with CBL, IRS1, PIK3R1 and PLCG1. Interacts with FRS2 and SHC1. Interacts with PTN and MDK (By similarity).
Family & Domains
Features
Showing features for compositional bias, region, domain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Compositional bias | 20-44 | Polar residues | ||||
Sequence: GSGAGTGSGTGSGTGTGTGQLVGSP | ||||||
Region | 20-53 | Disordered | ||||
Sequence: GSGAGTGSGTGSGTGTGTGQLVGSPATGPALQPR | ||||||
Region | 60-82 | Heparin-binding region | ||||
Sequence: RLQRKSLAVDFVVPSLFRVYARD | ||||||
Domain | 280-443 | MAM 1 | ||||
Sequence: LECSFDFPCELEYSPPLHDLGNQSWSWRRVPSEEASQMDLLDGPETEHSKEMPRGSFLLLNTSANSKHTILSPWMRSSSEHCKLAVSVHRHLQPSGRYVAQLLPHNEPGREILLVPTPGKHGWTVLQGRIGRPENPFRVALEYISSGNRSLSAVDFFALKNCSE | ||||||
Domain | 494-652 | MAM 2 | ||||
Sequence: FYCNFENGFCGWSQGILTPHNPRWQVRTLKDARVQDHRGHALSLSTTDVPTSESATVTSATFPAPMKNSPCELRMSWLIHGVLRGNVSLVLVENKTGKEQSRMVWHVATNEGLSLWQWTVLPLLDVADRFWLQIVAWWGQGSRATVAFDNISISLDCYL | ||||||
Region | 1002-1040 | EGF-like | ||||
Sequence: CSHCEGDECHMDPESHKVICFCDHGTVLAEDGVSCIVSP | ||||||
Domain | 1131-1407 | Protein kinase | ||||
Sequence: ITLIRGLGHGAFGEVYEGQVSGVPSDPSPLQVAVKTLPEVCSEQDELDFLMEALIISKFNHQNIVRCIGVSLQALPRFILLELMAGGDLKSFLRETRPRPNQPSSLAMLDLLHVAQDIACGCQYLEENHFIHRDIAARNCLLTCPGPGRVAKIGDFGMARDIYRASYYRKGGCAMLPVKWMPPEAFMEGIFTSKTDTWSFGVLLWEIFSLGYMPYPSKSNQEVLEFVTSGGRMDPPKNCPGPVYRIMTQCWQHQPEDRPNFAIILERIEYCTQDPDV | ||||||
Region | 1423-1493 | Disordered | ||||
Sequence: EEKVPMRPQDPEGIPPLLVSPPQAKREEGPDPAAPPPLPSTSSGKAAKKPTAAELSGRVTRGPAVEGGHVN | ||||||
Region | 1526-1554 | Disordered | ||||
Sequence: WFTEKPTKKNNPPATKGHHDRGNLGREGS | ||||||
Compositional bias | 1536-1550 | Basic and acidic residues | ||||
Sequence: NPPATKGHHDRGNLG | ||||||
Region | 1609-1631 | Disordered | ||||
Sequence: FEGTTAPGSSQYEDALLKTPPGP |
Domain
The EGF-like region drives the cytokine specificity for ALKAL2.
The heparin-binding region binds heparin glycosaminoglycan (PubMed:25605972).
Heparin-binding is required for ALKAL2-driven activation (By similarity).
Heparin-binding is required for ALKAL2-driven activation (By similarity).
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Sequence processingThe displayed sequence is further processed into a mature form.
- Length1,631
- Mass (Da)176,615
- Last updated2022-05-25 v1
- ChecksumFEEB10D03AF57C45
Computationally mapped potential isoform sequences
There is 1 potential isoform mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
A0A8I3NE96 | A0A8I3NE96_CANLF | ALK | 1631 |
Features
Showing features for compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Compositional bias | 20-44 | Polar residues | ||||
Sequence: GSGAGTGSGTGSGTGTGTGQLVGSP | ||||||
Compositional bias | 1536-1550 | Basic and acidic residues | ||||
Sequence: NPPATKGHHDRGNLG |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AAEX03010811 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
AAEX03010812 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
AAEX03010813 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. |