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Stability of the Peutz–Jeghers syndrome kinase LKB1 requires its binding to the molecular chaperones Hsp90/Cdc37

Oncogene volume 22, pages 9165–9175 (2003)Cite this article

Abstract

Peutz–Jeghers syndrome (PJS) is an autosomal dominant disorder characterized by the presence of multiple gastrointestinal polyps and an increased risk for various types of cancers. Inactivating germline mutations of the LKB1 gene, which encodes a serine/threonine kinase, are responsible for the majority of PJS cases. Here, we show that the heteromeric complex containing the molecular chaperones Hsp90 and Cdc37/p50 interacts with the kinase domain of LKB1. Treatment of cells with either geldanamycin or novobiocin, two pharmacological inhibitors of Hsp90 causes the destabilization of LKB1. Furthermore, geldanamycin treatment leads to the ubiquitination and the rapid degradation of LKB1 by the proteasome-dependent pathway. In addition, we found that a LKB1 point mutation identified in a sporadic testicular cancer, weakens the interaction of LKB1 with both Hsp90 and Cdc37/p50 and enhances its sensitivity to the destabilizing effect of geldanamycin. Collectively, our results demonstrate that the Hsp90/Cdc37 complex is a major regulator of the stability of the LKB1 tumor suppressor. Furthermore, these data draw attention to the possible adverse consequences of antitumor drugs that target Hsp90, such as antibiotics related to geldanamycin, which could disrupt LKB1 function and promote the development of polyps and carcinomatous lesions.

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Acknowledgements

We gratefully acknowledge Janet Hall for critical reading of the manuscript. We also thank Dirk Bohmann for the kind gift of the plasmid expressing HA-tagged ubiquitin. This work was supported by the Ligue Nationale Contre le Cancer (group Marc Billaud ‘labellisée’ by the Ligue Nationale Contre le Cancer). During this work, PN, HG and MR have been the recipients of a fellowship from the Ligue Nationale Contre le Cancer, Comité de Haute-Savoie and Ligue Nationale and from the Fondation pour la Recherche Médicale, respectively.

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  1. Laboratoire Génétique et Cancer, FRE 2692, Domaine Rockefeller, 8, avenue Rockefeller, Lyon, Cedex 08, 69373, France

    Pascale Nony, Hélène Gaude, Laurence Fournier & Marc Billaud

  2. Laboratoire Biologie Cellulaire Quantitative, Ecole Pratique des Hautes Etudes, INSERM E0343, Place E Bataillon, Montpellier, Cedex 05, 34095, France

    Mireille Rossel

  3. Laboratoire de Communications Cellulaires et Différenciation, Inserm U418, INRA UA 953, Hôpital Debrousse, 29 rue Sœur Bouvier, Lyon, Cedex 05, 69322, France

    Jean-Pierre Rouault

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  1. Pascale Nony
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Correspondence to Marc Billaud.

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Nony, P., Gaude, H., Rossel, M. et al. Stability of the Peutz–Jeghers syndrome kinase LKB1 requires its binding to the molecular chaperones Hsp90/Cdc37. Oncogene 22, 9165–9175 (2003). https://doi.org/10.1038/sj.onc.1207179

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