title: The NPM-ALK tyrosine kinase mimics TCR signalling pathways, inducing NFAT and AP-1 by RAS-dependent mechanisms.
abstract: Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) expression is associated with the lymphoid malignancy anaplastic large cell lymphoma (ALCL) and results from a t(2;5) chromosomal translocation. We show that NPM-ALK induces Ras activation and phosphorylation of the ERK MAP Kinase consistent with activation of the Ras-MAP Kinase pathway. Furthermore, we demonstrate that activation of Ras is necessary for inducing transcription via NFAT/AP-1 composite transcriptional binding sites. This activity is dependent on NPM-ALK forming complexes with proteins that bind to autophosphorylated tyrosine residues at positions 156, 567 and 664, associated with binding to IRS-1, Shc and PLCgamma, respectively. Specifically, NPM-ALK activates transcription from the TRE promoter element, an AP-1 binding region, an activity dependent on both Ras and Shc activity. Our results show that NPM-ALK mimics activated T-cell receptor signalling by inducing pathways associated with the activation of NFAT/AP-1 transcription factors that bind to promoter elements found in a broad array of cytokine genes.
authors.affiliation: Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK. sdt36@cam.ac.uk
authors.forename: Suzanne D
authors.initials: SD
authors.lastname: Turner
authors.forename: Debra
authors.initials: D
authors.lastname: Yeung
authors.forename: Kathryn
authors.initials: K
authors.lastname: Hadfield
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Cook
authors.forename: Denis R
authors.initials: DR
authors.lastname: Alexander
mesh_terms: D000818:Animals; D001665:Binding Sites; D002457:Cell Extracts; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D019169:Jurkat Cells; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D018716:Molecular Mimicry; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D002457:Cell Extracts; D050778:NFATC Transcription Factors; D011948:Receptors, Antigen, T-Cell; D018808:Transcription Factor AP-1; D008156:Luciferases; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins