A "liaison dangereuse" between AUF1/hnRNPD and the oncogenic tyrosine kinase NPM-ALK.
Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is a chimeric protein expressed in a subset of cases of anaplastic large cell lymphoma (ALCL) for which constitutive expression represents a key oncogenic event. The ALK signaling pathway is complex and probably involves functional redundancy between various signaling substrates of ALK. Despite numerous studies on signaling mediators, the molecular mechanisms contributing to the distinct oncogenic features of NPM-ALK remain incompletely understood. The search for additional interacting partners of NPM-ALK led to the discovery of AUF1/hnRNPD, a protein implicated in AU-rich element (ARE)-directed mRNA decay. AUF1 was immunoprecipitated with ALK both in ALCL-derived cells and in NIH3T3 cells stably expressing NPM-ALK or other X-ALK fusion proteins. AUF1 and NPM-ALK were found concentrated in the same cytoplasmic foci, whose formation required NPM-ALK tyrosine kinase activity. AUF1 was phosphorylated by ALK in vitro and was hyperphosphorylated in NPM-ALK-expressing cells. Its hyperphosphorylation was correlated with increased stability of several AUF1 target mRNAs encoding key regulators of cell proliferation and with increased cell survival after transcriptional arrest. Thus, AUF1 could function in a novel pathway mediating the oncogenic effects of NPM-ALK. Our data establish an important link between oncogenic kinases and mRNA turnover, which could constitute a critical aspect of tumorigenesis.
Fawal
Mohamad
M
Centre de Biologie du Développement, CNRS-UMR 5547, IFR 109, Université Paul Sabatier, Bâtiment 4R3, 118 Route de Narbonne, 31062 Toulouse Cedex 4, France.
Armstrong
Florence
F
Ollier
Severine
S
Dupont
Henri
H
Touriol
Christian
C
Monsarrat
Bernard
B
Delsol
Georges
G
Payrastre
Bernard
B
Morello
Dominique
D
D000595:Amino Acid Sequence; D000818:Animals; D016923:Cell Death; D016213:Cyclins / Q000235:genetics; D016259:Genes, myc; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000378:metabolism*; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D016213:Cyclins; C000630986:HNRNPD protein, human; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; C000630987:Hnrpd protein, mouse; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases