Heat-shock protein 90 and Cdc37 interact with LKB1 and regulate its stability.
LKB1 is a widely expressed serine/threonine protein kinase that is mutated in the inherited Peutz-Jeghers cancer syndrome. Recent findings indicate that LKB1 functions as a tumour suppressor, but little is known regarding the detailed mechanism by which LKB1 regulates cell growth. In this study we have purified LKB1 from cells and establish that it is associated with the heat-shock protein 90 (Hsp90) chaperone and the Cdc37 kinase-specific targetting subunit for Hsp90. We demonstrate that Cdc37 and Hsp90 bind specifically to the kinase domain of LKB1. We also perform experiments using Hsp90 inhibitors, which indicate that the association of Hsp90 and Cdc37 with LKB1 regulates LKB1 stability and prevents its degradation by the proteasome. Hsp90 inhibitors are being considered as potential anti-cancer agents. However, our observations indicate that prolonged usage of these drugs could possibly lead to tumour development by decreasing cellular levels of LKB1.
Boudeau
Jérôme
J
MRC Protein Phosphorylation Unit, MSI/WTB Complex, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK. j.bordeau@dundee.ac.uk
Deak
Maria
M
Lawlor
Margaret A
MA
Morrice
Nick A
NA
Alessi
Dario R
DR
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000818:Animals; D016227:Benzoquinones; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D018833:Chaperonins; D003546:Cysteine Endopeptidases / Q000378:metabolism; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors / Q000378:metabolism; D004795:Enzyme Stability; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic; D007783:Lactones / Q000378:metabolism; D018942:Macrolides; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism; D010580:Peutz-Jeghers Syndrome / Q000201:enzymology; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011809:Quinones / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
D016227:Benzoquinones; C498362:CDC37 protein, human; C513271:Cdc37 protein, mouse; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D007783:Lactones; D018942:Macrolides; D018832:Molecular Chaperones; D009097:Multienzyme Complexes; D011809:Quinones; D011993:Recombinant Fusion Proteins; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C491654:Stk11 protein, mouse; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D018833:Chaperonins; C035359:monorden; C001277:geldanamycin