The enzymatic activity of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase is enhanced by NPM-ALK: new insights in ALK-mediated pathogenesis and the treatment of ALCL

Autor: Ludovica Riera, Michael J. Comb, Claudia Voena, Giorgio Inghirami, Francesco Boccalatte, Amalia Bosia, Ole N. Jensen, Roberto D. Polakiewicz, John Rush, Julie Nardone, Valerie Goss, Bruce Ruggeri, Mangeng Cheng, Kimberly Lee, Roberto Chiarle, Chiara Riganti, Lucia D'Amico
Rok vydání: 2009
Předmět:
Hydroxymethyl and Formyl Transferases
Antimetabolites
Antineoplastic
Indazoles
Transcription
Genetic
Molecular Sequence Data
Immunology
Carbazoles
Biology
Biochemistry
03 medical and health sciences
0302 clinical medicine
Multienzyme Complexes
RNA interference
Cell Line
Tumor
hemic and lymphatic diseases
Protein Interaction Mapping
medicine
Humans
Anaplastic lymphoma kinase
Amino Acid Sequence
Phosphorylation
Phosphotyrosine
Protein Kinase Inhibitors
Anaplastic large-cell lymphoma
030304 developmental biology
0303 health sciences
Kinase
Gene Expression Profiling
Phenylurea Compounds
Microfilament Proteins
IMP cyclohydrolase
Cell Biology
Hematology
Protein-Tyrosine Kinases
Phosphoproteins
medicine.disease
Molecular biology
Fusion protein
Neoplasm Proteins
Methotrexate
Drug Resistance
Neoplasm
Nucleotide Deaminases
030220 oncology & carcinogenesis
Cancer research
Lymphoma
Large-Cell
Anaplastic
Cell Adhesion Molecules
Protein Processing
Post-Translational
Tyrosine kinase
Zdroj: Boccalatte, F E, Voena, C, Riganti, C, Bosia, A, D'Amico, L, Riera, L, Cheng, M, Ruggeri, B, Jensen, O N, Goss, V L, Lee, K, Nardone, J, Rush, J, Polakiewicz, R D, Comb, M J, Chiarle, R & Inghirami, G 2009, ' The enzymatic activity of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC) is enhanced by NPM-ALK : new insights in ALK-mediated pathogenesis and the treatment of ALCL ', Blood, vol. 8, no. 3, pp. 2776-2790 . https://doi.org/10.1182/blood-2008-06-161018
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood-2008-06-161018
Popis: Anaplastic large cell lymphoma represents a subset of neoplasms caused by translocations that juxtapose the anaplastic lymphoma kinase (ALK) to dimerization partners. The constitutive activation of ALK fusion proteins leads to cellular transformation through a complex signaling network. To elucidate the ALK pathways sustaining lymphomagenesis and tumor maintenance, we analyzed the tyrosine-kinase protein profiles of ALK-positive cell lines using 2 complementary proteomic-based approaches, taking advantage of a specific ALK RNA interference (RNAi) or cell-permeable inhibitors. A well-defined set of ALK-associated tyrosine phosphopeptides, including metabolic enzymes, kinases, ribosomal and cytoskeletal proteins, was identified. Validation studies confirmed that vasodilator-stimulated phosphoprotein and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC) associated with nucleophosmin (NPM)–ALK, and their phosphorylation required ALK activity. ATIC phosphorylation was documented in cell lines and primary tumors carrying ALK proteins and other tyrosine kinases, including TPR-Met and wild type c-Met. Functional analyses revealed that ALK-mediated ATIC phosphorylation enhanced its enzymatic activity, dampening the methotrexate-mediated transformylase activity inhibition. These findings demonstrate that proteomic approaches in well-controlled experimental settings allow the definition of informative proteomic profiles and the discovery of novel ALK downstream players that contribute to the maintenance of the neoplastic phenotype. Prediction of tumor responses to methotrexate may justify specific molecular-based chemotherapy.
Databáze: OpenAIRE
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