Anaplastic lymphoma kinase

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Anaplastic lymphoma kinase
Anaplastic lymphoma kinase
from PDB  2XP2
Mass / length primary structure 1,620 amino acids , 176,442 Da
Identifier
External IDs
Enzyme classification
EC, category 2.7.10.1
Orthologue
human mouse
Entrez 238 11682
Ensemble ENSG00000171094 ENSMUSG00000055471
UniProt Q9UM73 P97793
Refseq (mRNA) NM_001353765.1 NM_007439
Refseq (protein) NP_001340694.1 NP_031465
Gene locus Chr 2: 29.19 - 29.92 Mb
PubMed search 238 11682

The anaplastic lymphoma kinase (ALK, CD246, NBLST3, English: anaplastic lymphoma kinase ) is a receptor tyrosine kinase of the insulin receptor superfamily in animals and a proto-oncogene .

properties

ALK is a neural receptor tyrosine kinase that is expressed essentially and transiently in certain regions of the central and peripheral nervous system and plays an important role in the formation and differentiation of the nervous system. It redirects signals from ligands on the cell surface through specific activation of the mitogen-activated protein kinase pathway ( MAP kinase pathway ). ALK phosphorylates almost exclusively on the first tyrosine of the YxxxxYY motif. After activation by a ligand, ALK induces the tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1 as well as the MAP kinases MAPK1 / ERK2 and MAPK3 / ERK1. It acts as a receptor for the ligands pleiotropin (PTN), a secreted growth factor , and midkine (MDK), a PTN-related factor, and is thus involved in PTN and MDK signal transduction . PTN binding induces the activation of the MAPK signaling pathway, which is important for anti-apoptotic signal transmission by PTN and the 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 , which also leads to the induction of cell proliferation. ALK drives NF-kappa-B activation, probably through IRS1 and the activation of AKT-serine / threonine kinase. The recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signal transduction of MDK. ALK comprises an extracellular domain , a hydrophobic portion corresponding to a single passage transmembrane region , and an intracellular kinase domain . The tyrosine kinase domain of ALK is homologous to the insulin receptor, whereas the extracellular domain is unique among the receptor tyrosine kinases and contains two MAM protein domains (named after Meprin , A5 protein and tyrosine phosphatase Mu), an LDLa protein domain and a glycine- rich domain. Over its entire length, ALK is most closely related to the leukocyte receptor tyrosine kinase (LTK). CH5424802 is a selective ALK inhibitor .

Anaplastic lymphoma kinase has been described in various animal species, including Drosophila melanogaster (as dAlk, 2001), Caenorhabditis elegans (as scd-2, 2004), and Danio rerio (as DrAlk, 2013).

Pathobiochemistry

ALK is rearranged , mutated, or amplified in a number of tumors , including anaplastic large cell lymphomas , neuroblastomas, and non-small cell lung cancer . The chromosomal rearrangements are the most common genetic alterations in ALK gene , which result in tumor development in the formation of multiple fusion genes, 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).

ALK is being investigated in connection with obesity , since a gene knockout of ALK in mice leads to reduced triglycerides , but to more free fatty acids and glycerol in the blood, and these mice become resistant to food-induced obesity .

history

The anaplastic lymphoma kinase was first described in 1994 in anaplastic large cell lymphomas as part of the fusion protein ALK / NPM1. The unmutated ALK was first described in 1997.

Individual evidence

  1. ↑ a b ALK - ALK tyrosine kinase receptor precursor - Homo sapiens (Human) - ALK gene & protein. In: uniprot.org. May 18, 2010, accessed May 26, 2020 .
  2. Jump up ↑ a b c Morris SW, Naeve C, Mathew P, James PL, Kirstein MN, Cui X, Witte DP: ALK, the chromosome 2 gene locus altered by the t (2; 5) in non-Hodgkin's lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK) . In: Oncogene . 14, No. 18, May 1997, pp. 2175-88. doi : 10.1038 / sj.onc.1201062 . PMID 9174053 .
  3. ↑ a b Lorén CE, Scully A, Grabbe C, Edeen PT, Thomas J, McKeown M, Hunter T, Palmer RH: Identification and characterization of DAlk: a novel Drosophila melanogaster RTK which drives ERK activation in vivo . In: Genes to Cells . 6, No. 6, June 2001, pp. 531-44. doi : 10.1046 / j.1365-2443.2001.00440.x . PMID 11442633 . PMC 1975818 (free full text).
  4. ↑ a b Iwahara T, Fujimoto J, Wen D, Cupples R, Bucay N, Arakawa T, Mori S, Ratzkin B, Yamamoto T: Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system . In: Oncogene . 14, No. 4, January 1997, pp. 439-49. doi : 10.1038 / sj.onc.1200849 . PMID 9053841 .
  5. ↑ H. Sakamoto, T. Tsukaguchi, S. Hiroshima, T. Kodama, T. Kobayashi, TA Fukami, N. Oikawa, T. Tsukuda, N. Ishii, Y. Aoki: CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. In: Cancer cell. Volume 19, number 5, May 2011, pp. 679-690, doi : 10.1016 / j.ccr.2011.04.004 , PMID 21575866 .
  6. ↑ Liao EH, Hung W, Abrams B, Zhen M: An SCF-like ubiquitin ligase complex that controls presynaptic differentiation . In: Nature . 430, No. 6997, July 2004, pp. 345-50. bibcode : 2004Natur.430..345L . doi : 10.1038 / nature02647 . PMID 15208641 .
  7. ↑ Yao S, Cheng M, Zhang Q, Wasik M, Kelsh R, Winkler C: Anaplastic lymphoma kinase is required for neurogenesis in the developing central nervous system of zebrafish . In: PLOS ONE . 8, No. 5, May 2013, p. E63757. bibcode : 2013PLoSO ... 863757Y . doi : 10.1371 / journal.pone.0063757 . PMID 23667670 . PMC 3648509 (free full text).
  8. ↑ Michael Orthofer, Armand Valsesia, Reedik Mägi, Qiao-Ping Wang, Joanna Kaczanowska, Ivona Kozieradzki, Alexandra Leopoldi, Domagoj Cikes, Lydia M. Zopf, Evgenii O. Tretiakov, Egon Demetz, Richard Hilbe, Anna Boehm, Melita Ticevic, Margit Nõukas, Alexander Jais, Katrin Spirk, Teleri Clark, Sabine Amann, Maarja Lepamets, Christoph Neumayr, Cosmas Arnold, Zhengchao Dou, Volker Kuhn, Maria Novatchkova, Shane JF Cronin, Uwe JF Tietge, Simone Müller, J. Andrew Pospisilik, Vanja Nagy , Chi-Chung Hui, Jelena Lazovic, Harald Esterbauer, Astrid Hagelkruys, Ivan Tancevski, Florian W. Kiefer, Tibor Harkany, Wulf Haubensak, G. Gregory Neely, Andres Metspalu, Jorg Hager, Nele Gheldof, Josef M. Penninger: Identification of ALK in Thinness. In: Cell. 2020, doi : 10.1016 / j.cell.2020.04.034 .
  9. Jump up ↑ SW Morris, MN Kirstein, MB Valentine, KG Dittmer, DN Shapiro, DL Saltman, AT Look: Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. In: Science . Volume 263, Number 5151, March 1994, pp. 1281-1284, doi : 10.1126 / science.8122112 , PMID 8122112 .
  10. ↑ Shiota M, Fujimoto J, Semba T, Satoh H, Yamamoto T, Mori S: Hyperphosphorylation of a novel 80 kDa protein-tyrosine kinase similar to Ltk in a human Ki-1 lymphoma cell line, AMS3 . In: Oncogene . 9, No. 6, June 1994, pp. 1567-74. PMID 8183550 .