Anaplastic lymphoma kinase
Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246) is an enzyme that in humans is encoded by the ALK gene. Anaplastic lymphoma kinase (ALK) was originally discovered in 1994 in anaplastic large-cell lymphoma (ALCL) cells. ALCL is caused by a (2;5)(p23:q35) chromosomal translocation that generates the fusion protein NPM-ALK, in which the kinase domain of ALK is fused to the amino-terminal part of the nucleophosmin (NPM) protein. Dimerization of NPM constitutively activates the ALK kinase domain. The full-length protein ALK was identified in 1997 by two groups. The deduced amino acid sequences revealed that ALK was a novel receptor tyrosine kinase (RTK), having an extracellular ligand-binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain. While the tyrosine kinase domain of human ALK shares a high degree of similarity with that of the insulin receptor, its extracellular domain is unique among the RTK family in containing two MAM domains (meprin, A5 protein and receptor protein tyrosine phosphatase mu), an LDLa domain (low-density lipoprotein receptor class A) and a glycine-rich region. Based on overall homology, ALK is closely related to the leukocyte receptor tyrosine kinase (LTK) and, together with the insulin receptor, forms a subgroup in the RTK superfamily. The human ALK gene encodes a protein 1,620 amino acids long with a molecular weight of 180 kDa. Since the original discovery of the receptor in mammals, several orthologs of ALK have been identified: dAlk in the fruit fly (Drosophila melanogaster) in 2001, scd-2 in the nematode (Caenorhabditis elegans) in 2004, and DrAlk in the zebrafish (Danio rerio) in 2013. The ligands of the human ALK/LTK receptors were identified in 2014: FAM150A (AUGβ) and FAM150B (AUGα), two small secreted peptides that strongly activate ALK signaling. In invertebrates, ALK-activating ligands are Jelly belly (Jeb) in Drosophila, and hesitation behaviour 1 (HEN-1) in C. elegans.
