Blood Journal
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A “liaison dangereuse” between AUF1/hnRNPD and the oncogenic tyrosine kinase NPM-ALK

  1. Mohamad Fawal,
  2. Florence Armstrong,
  3. Severine Ollier,
  4. Henri Dupont,
  5. Christian Touriol,
  6. Bernard Monsarrat,
  7. Georges Delsol,
  8. Bernard Payrastre, and
  9. Dominique Morello
  1. From the Centre de Biologie du Développement (CBD), Centre National de la Recherche Scientifique (CNRS)-Unité Mixte de Recherche (UMR) 5547, Institut Fédératif de Recherche (IFR) 109, Université Paul Sabatier, Toulouse; Institut National de la Santé et de la Recherche Médicale (INSERM) U563, “Département d'Oncogenèse et Signalisation dans les Cellules Hématopoïétiques,” Hôpital Purpan, Toulouse; INSERM Unité 589, Centre Hospitalo-Universitaire (CHU) Rangueil, Toulouse; and Institut de Pharmacologie et de Biologie Structurale (IPBS), UMR 5089, Toulouse, France.

Abstract

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.

  • Submitted April 5, 2006.
  • Accepted June 11, 2006.
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