InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: ALK

Summary

InnateDB Protein

IDBP-42088.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

ALK

Protein Name

anaplastic lymphoma receptor tyrosine kinase

Synonyms

CD246; NBLST3;

Species

Homo sapiens

Ensembl Protein

ENSP00000373700

InnateDB Gene

IDBG-42084 (ALK)

Protein Structure

UniProt Annotation

Function

Neuronal orphan 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. Transduces signals from ligands at the cell surface, through specific 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. Following activation by ligand, ALK induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Acts as a receptor for ligands pleiotrophin (PTN), a secreted growth factor, and midkine (MDK), a PTN-related factor, thus participating in PTN and MDK signal transduction. 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. {ECO:0000269PubMed:11121404, ECO:0000269PubMed:11278720, ECO:0000269PubMed:11387242, ECO:0000269PubMed:11809760, ECO:0000269PubMed:12107166, ECO:0000269PubMed:12122009, ECO:0000269PubMed:15226403, ECO:0000269PubMed:15908427, ECO:0000269PubMed:16317043, ECO:0000269PubMed:16878150, ECO:0000269PubMed:17274988}.

Subcellular Localization

Cell membrane {ECO:0000269PubMed:16317043, ECO:0000269PubMed:9174053}; Single-pass type I membrane protein {ECO:0000269PubMed:16317043, ECO:0000269PubMed:9174053}. Note=Membrane attachment was crucial for promotion of neuron-like differentiation and cell proliferation arrest through specific activation of the MAP kinase pathway.

Disease Associations

Note=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.Note=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.Note=A chromosomal aberration involving ALK is associated with anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25) with ALO17.Neuroblastoma 3 (NBLST3) [MIM:613014]: A common neoplasm of early childhood arising from embryonic cells that form the primitive neural crest and give rise to the adrenal medulla and the sympathetic nervous system. {ECO:0000269PubMed:18724359, ECO:0000269PubMed:18923523, ECO:0000269PubMed:18923525}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.Note=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.

Tissue Specificity

Expressed in brain and CNS. Also expressed in the small intestine and testis, but not in normal lymphoid cells. {ECO:0000269PubMed:9174053}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 58 experimentally validated interaction(s) in this database.
They are also associated with 2 interaction(s) predicted by orthology.

Experimentally validated
Total	58 [view]
Protein-Protein	58 [view]
Protein-DNA	0
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	2 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0004672	protein kinase activity
GO:0004704	NF-kappaB-inducing kinase activity
GO:0004713	protein tyrosine kinase activity
GO:0004714	transmembrane receptor protein tyrosine kinase activity
GO:0005515	protein binding
GO:0005524	ATP binding
GO:0016772	transferase activity, transferring phosphorus-containing groups

Biological Process

GO:0000187	activation of MAPK activity
GO:0006468	protein phosphorylation
GO:0007165	signal transduction
GO:0007169	transmembrane receptor protein tyrosine kinase signaling pathway
GO:0007399	nervous system development
GO:0008283	cell proliferation
GO:0016310	phosphorylation
GO:0018108	peptidyl-tyrosine phosphorylation
GO:0038061	NIK/NF-kappaB signaling
GO:0042981	regulation of apoptotic process
GO:0046777	protein autophosphorylation
GO:0048666	neuron development
GO:0051092	positive regulation of NF-kappaB transcription factor activity

Cellular Component

GO:0005887	integral component of plasma membrane
GO:0016020	membrane
GO:0043234	protein complex
GO:0070062	extracellular vesicular exosome

Protein Structure and Domains

PDB ID

InterPro

IPR000719 Protein kinase domain
IPR000998 MAM domain
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR002172 Low-density lipoprotein (LDL) receptor class A repeat
IPR002290 Serine/threonine/dual specificity protein kinase, catalytic domain
IPR008985 Concanavalin A-like lectin/glucanases superfamily
IPR011009 Protein kinase-like domain
IPR020635 Tyrosine-protein kinase, catalytic domain

PFAM

PF00069
PF00629
PF07714
PF00057

PRINTS

PR00020
PR00109
PR00261

PIRSF

SMART

SM00137
SM00192
SM00220
SM00219

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt