Stability of the Peutz-Jeghers syndrome kinase LKB1 requires its binding to the molecular chaperones Hsp90/Cdc37.
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.
Nony
Pascale
P
Laboratoire Génétique et Cancer, FRE 2692, Domaine Rockefeller, 8, avenue Rockefeller, 69373 Lyon Cedex 08, France.
Gaude
Hélène
H
Rossel
Mireille
M
Fournier
Laurence
L
Rouault
Jean-Pierre
JP
Billaud
Marc
M
D000091162:AMP-Activated Protein Kinase Kinases; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000633:toxicity; D016227:Benzoquinones; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D018833:Chaperonins; D029721:Drosophila Proteins; D004795:Enzyme Stability; D016147:Genes, Tumor Suppressor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D047029:Lactams, Macrocyclic; D008297:Male; D018832:Molecular Chaperones / Q000737:chemistry / Q000378:metabolism*; D009675:Novobiocin / Q000494:pharmacology; D010580:Peutz-Jeghers Syndrome / Q000201:enzymology* / Q000235:genetics; D017354:Point Mutation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D011809:Quinones / Q000494:pharmacology; D013736:Testicular Neoplasms / Q000235:genetics
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D016227:Benzoquinones; C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018832:Molecular Chaperones; D011809:Quinones; D009675:Novobiocin; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D018833:Chaperonins; C001277:geldanamycin