ALK

This gene encodes a receptor tyrosine kinase, which belongs to the insulin receptor superfamily. This protein comprises an extracellular domain, an hydrophobic stretch corresponding to a single pass transmembrane region, and an intracellular kinase domain. It plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system. This gene has been found to be rearranged, mutated, or amplified in a series of tumours including anaplastic large cell lymphomas, neuroblastoma, and non-small cell lung cancer. The chromosomal rearrangements are the most common genetic alterations in this gene, which result in creation of multiple fusion genes in tumourigenesis, including ALK (chromosome 2)/EML4 (chromosome 2), ALK/RANBP2 (chromosome 2), ALK/ATIC (chromosome 2), ALK/TFG (chromosome 3), ALK/NPM1 (chromosome 5), ALK/SQSTM1 (chromosome 5), ALK/KIF5B (chromosome 10), ALK/CLTC (chromosome 17), ALK/TPM4 (chromosome 19), and ALK/MSN (chromosome X).[provided by RefSeq, Jan 2011]

Full Name

ALK Receptor Tyrosine Kinase

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. 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. Thinness gene 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).

Biological Process

Activation of MAPK activity Source: UniProtKB
Adult behavior Source: Ensembl
Energy homeostasis Source: UniProtKB
Hippocampus development Source: Ensembl
Multicellular organism development Source: GO_Central
Negative regulation of lipid catabolic process Source: UniProtKB
Neuron development Source: UniProtKB
Phosphorylation Source: UniProtKB
Positive regulation of dendrite development Source: UniProtKB
Positive regulation of kinase activity Source: GO_Central
Positive regulation of NF-kappaB transcription factor activity Source: UniProtKB
Protein autophosphorylation Source: UniProtKB
Regulation of apoptotic process Source: UniProtKB
Regulation of cell population proliferation Source: GO_Central
Regulation of dopamine receptor signaling pathway Source: Ensembl
Regulation of neuron differentiation Source: GO_Central
Response to environmental enrichment Source: Ensembl
Signal transduction Source: UniProtKB
Swimming behavior Source: Ensembl
Transmembrane receptor protein tyrosine kinase signaling pathway Source: GO_Central

Cellular Location

Cell membrane. Membrane attachment was crucial for promotion of neuron-like differentiation and cell proliferation arrest through specific activation of the MAP kinase pathway.

Involvement in 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.
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.
A chromosomal aberration involving ALK is associated with anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25) with ALO17.
Neuroblastoma 3 (NBLST3): 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.

Topology

Extracellular: 19-1038 aa
Helical: 1039-1059 aa
Cytoplasmic: 1060-1620 aa

PTM

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. Phosphorylation at Tyr-1507 is critical for SHC1 association.
N-glycosylated.