P0DV84 · ALK_CANLF

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).

Catalytic activity

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).

Features

Showing features for binding site, active site.

TypeIDPosition(s)Description
Binding site1137-1145ATP (UniProtKB | ChEBI)
Binding site1165ATP (UniProtKB | ChEBI)
Active site1264Proton acceptor

GO annotations

AspectTerm
Cellular Componentplasma membrane
Cellular Componentreceptor complex
Molecular FunctionATP binding
Molecular Functiontransmembrane receptor protein tyrosine kinase activity
Biological Processcell surface receptor protein tyrosine kinase signaling pathway
Biological Processregulation of cell population proliferation
Biological Processregulation of neuron differentiation

Keywords

Enzyme and pathway databases

Names & Taxonomy

Protein names

  • Recommended name
    ALK tyrosine kinase receptor
  • EC number

Gene names

    • Name
      ALK

Organism names

Accessions

  • Primary accession
    P0DV84

Proteomes

Subcellular Location

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.

TypeIDPosition(s)Description
Topological domain19-1053Extracellular
Transmembrane1054-1074Helical
Topological domain1075-1631Cytoplasmic

Keywords

PTM/Processing

Features

Showing features for signal, chain, glycosylation, disulfide bond.

TypeIDPosition(s)Description
Signal1-18
ChainPRO_502387422019-1631ALK tyrosine kinase receptor
Glycosylation185N-linked (GlcNAc...) asparagine
Glycosylation260N-linked (GlcNAc...) asparagine
Glycosylation301N-linked (GlcNAc...) asparagine
Glycosylation340N-linked (GlcNAc...) asparagine
Glycosylation427N-linked (GlcNAc...) asparagine
Glycosylation440N-linked (GlcNAc...) asparagine
Glycosylation461N-linked (GlcNAc...) asparagine
Glycosylation579N-linked (GlcNAc...) asparagine
Glycosylation587N-linked (GlcNAc...) asparagine
Glycosylation643N-linked (GlcNAc...) asparagine
Disulfide bond703↔716
Glycosylation724N-linked (GlcNAc...) asparagine
Disulfide bond798↔809
Glycosylation823N-linked (GlcNAc...) asparagine
Glycosylation878N-linked (GlcNAc...) asparagine
Glycosylation879N-linked (GlcNAc...) asparagine
Glycosylation901N-linked (GlcNAc...) asparagine
Disulfide bond921↔943
Glycosylation1001N-linked (GlcNAc...) asparagine
Disulfide bond1002↔1010
Disulfide bond1005↔1021
Disulfide bond1023↔1036

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 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).

Structure

3D structure databases

Family & Domains

Features

Showing features for compositional bias, region, domain.

TypeIDPosition(s)Description
Compositional bias20-44Polar residues
Region20-53Disordered
Region60-82Heparin-binding region
Domain280-443MAM 1
Domain494-652MAM 2
Region1002-1040EGF-like
Domain1131-1407Protein kinase
Region1423-1493Disordered
Region1526-1554Disordered
Compositional bias1536-1550Basic and acidic residues
Region1609-1631Disordered

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).

Keywords

Phylogenomic databases

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Sequence processing
    The displayed sequence is further processed into a mature form.
  • Length
    1,631
  • Mass (Da)
    176,615
  • Last updated
    2022-05-25 v1
  • Checksum
    FEEB10D03AF57C45
MGSVGLLGLLLLRLSVTASGSGAGTGSGTGSGTGTGTGQLVGSPATGPALQPREPLSYSRLQRKSLAVDFVVPSLFRVYARDLLLPPWSSSEPRAGWTEARGSLALDCAPLLRLLGPPPGVSWAEGASSPAPAQARTLTRVLKGGSVRKLRRAKQLVLELGEEAILEGCVGPSPEEVTAGLLQFNLSELFSWWIRHGEGRLRIRLMPEKKASAVGREGRLSAAIRASQPRLLFQILGTGHSSLESPTSLPSPPPDPFAWNLTWIMKDSFPFLSHRSRYGLECSFDFPCELEYSPPLHDLGNQSWSWRRVPSEEASQMDLLDGPETEHSKEMPRGSFLLLNTSANSKHTILSPWMRSSSEHCKLAVSVHRHLQPSGRYVAQLLPHNEPGREILLVPTPGKHGWTVLQGRIGRPENPFRVALEYISSGNRSLSAVDFFALKNCSEGTSPGSKMALQSSFTCWNGTVLQLGQACDFHQDCAQGEDEGQLCSQLPAGFYCNFENGFCGWSQGILTPHNPRWQVRTLKDARVQDHRGHALSLSTTDVPTSESATVTSATFPAPMKNSPCELRMSWLIHGVLRGNVSLVLVENKTGKEQSRMVWHVATNEGLSLWQWTVLPLLDVADRFWLQIVAWWGQGSRATVAFDNISISLDCYLTISGEEKMLQNTAPKSRNLFERNPNKDPRPWENTRETPVFDPTVHWLFTTCGASGPHGPTQAQCNNAYRNSNLSVVVGSEGPLKGIQTWKVPATDTYSISGYGAAGGKGGKNTMMRSHGVSVLGIFNLEKGDTLYILVGQQGEDACPSTNRLIQKVCIGENNVIEEEIRVNRSVHEWAGGGGGGGGATYVFKMKDGVPVPLIIAAGGGGRAYGAKTDTFHPERLENNSSVLGLNGNSGAAGGGGGWNDNTSLLWSGKSLLEGATGGHSCPQAMKKWGWETRGGFGGGGGGCSSGGGGGGYIGGNAASNNDPEMDGEDGVSFISPLGILYTPALKVMEGHGEVNIKHYLNCSHCEGDECHMDPESHKVICFCDHGTVLAEDGVSCIVSPTPEPHLPLSLVLSVVTSALVAALVLAFSGIMIVYRRKHQELQAMQMELQSPEYKLSKLRTSTIMTDYNPNYCFAGKTSSISDLKEVPRKNITLIRGLGHGAFGEVYEGQVSGVPSDPSPLQVAVKTLPEVCSEQDELDFLMEALIISKFNHQNIVRCIGVSLQALPRFILLELMAGGDLKSFLRETRPRPNQPSSLAMLDLLHVAQDIACGCQYLEENHFIHRDIAARNCLLTCPGPGRVAKIGDFGMARDIYRASYYRKGGCAMLPVKWMPPEAFMEGIFTSKTDTWSFGVLLWEIFSLGYMPYPSKSNQEVLEFVTSGGRMDPPKNCPGPVYRIMTQCWQHQPEDRPNFAIILERIEYCTQDPDVINTALPVEYGPLMEEEEKVPMRPQDPEGIPPLLVSPPQAKREEGPDPAAPPPLPSTSSGKAAKKPTAAELSGRVTRGPAVEGGHVNMAFSQSNPASELHKVQGSRNKPTSLWNPTYGSWFTEKPTKKNNPPATKGHHDRGNLGREGSCTVPPNVAAGRLPGASLLLEPSSLTASMKEVPLFRLRHFPCGNVNYGYQQQGLPFEGTTAPGSSQYEDALLKTPPGP

Computationally mapped potential isoform sequences

There is 1 potential isoform mapped to this entry

View all
EntryEntry nameGene nameLength
A0A8I3NE96A0A8I3NE96_CANLFALK1631

Features

Showing features for compositional bias.

TypeIDPosition(s)Description
Compositional bias20-44Polar residues
Compositional bias1536-1550Basic and acidic residues

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
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.

Genome annotation databases

Similar Proteins

Disclaimer

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