Submitted April 5, 2006
Accepted June 11, 2006
"Liaison dangereuse" between AUF1/hnRNPD and the oncogenic
tyrosine kinase NPM-ALK
Mohamad Fawal, Florence Armstrong, Severine Ollier, Henri Dupont, Christian Touriol, Bernard Monsarrat, Georges Delsol, Bernard Payrastre, and Dominique Morello*
CBD, CNRS UMR 5547, Universite Paul Sabatier, Toulouse Cedex, France
Department d'Oncogenese et Signalisation dans les Cellules Hematopoietiques, Hopital Purpan, France
INSERM Unite 589, CHU Rangueil, Toulouse Cedex, France
IPBS, UMR 5089, Toulouse Cedex 9, France
* Corresponding author; email: morello{at}cict.fr.
Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is a chimeric protein expressed in a subset of cases of anaplastic large cell lymphoma (ALCLs), for which constitutive expression represents a key oncogenic event. The ALK signalling pathway is complex and probably involves functional redundancy between various signalling substrates of ALK. Despite numerous studies on signalling 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.
