title: Molecular chaperone complexes with antagonizing activities regulate stability and activity of the tumor suppressor LKB1.
abstract: LKB1 is a tumor suppressor that is constitutionally mutated in a cancer-prone condition, called Peutz-Jeghers syndrome, as well as somatically inactivated in a sizeable fraction of lung and cervical neoplasms. The LKB1 gene encodes a serine/threonine kinase that associates with the pseudokinase STRAD (STE-20-related pseudokinase) and the scaffolding protein MO25, the formation of this heterotrimeric complex promotes allosteric activation of LKB1. We have previously reported that the molecular chaperone heat shock protein 90 (Hsp90) binds to and stabilizes LKB1. Combining pharmacological studies and RNA interference approaches, we now provide evidence that the co-chaperone Cdc37 participates to the regulation of LKB1 stability. It is known that the Hsp90-Cdc37 complex recognizes a surface within the N-terminal catalytic lobe of client protein kinases. In agreement with this finding, we found that the chaperones Hsp90 and Cdc37 interact with an LKB1 isoform that differs in the C-terminal region, but not with a novel LKB1 variant that lacks a portion of the kinase N-terminal lobe domain. Reconstitution of the two complexes LKB1-STRAD and LKB1-Hsp90-Cdc37 with recombinant proteins revealed that the former is catalytically active whereas the latter is inactive. Furthermore, consistent with a documented repressor function of Hsp90, LKB1 kinase activity was transiently stimulated upon dissociation of Hsp90. Finally, disruption of the LKB1-Hsp90 complex favors the recruitment of both Hsp/Hsc70 and the U-box dependent E3 ubiquitin ligase CHIP (carboxyl terminus of Hsc70-interacting protein) that triggers LKB1 degradation. Taken together, our results establish that the Hsp90-Cdc37 complex controls both the stability and activity of the LKB1 kinase. This study further shows that two chaperone complexes with antagonizing activities, Hsp90-Cdc37 and Hsp/Hsc70-CHIP, finely control the cellular level of LKB1 protein.
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, INSERM U1052/CNRS UMR 5286, Lyon, France.
authors.forename: H
authors.initials: H
authors.lastname: Gaude
authors.forename: N
authors.initials: N
authors.lastname: Aznar
authors.forename: A
authors.initials: A
authors.lastname: Delay
authors.forename: A
authors.initials: A
authors.lastname: Bres
authors.forename: K
authors.initials: K
authors.lastname: Buchet-Poyau
authors.forename: C
authors.initials: C
authors.lastname: Caillat
authors.forename: A
authors.initials: A
authors.lastname: Vigouroux
authors.forename: C
authors.initials: C
authors.lastname: Rogon
authors.forename: A
authors.initials: A
authors.lastname: Woods
authors.forename: J-M
authors.initials: JM
authors.lastname: Vanacker
authors.forename: J
authors.initials: J
authors.lastname: Höhfeld
authors.forename: C
authors.initials: C
authors.lastname: Perret
authors.forename: P
authors.initials: P
authors.lastname: Meyer
authors.forename: M
authors.initials: M
authors.lastname: Billaud
authors.forename: C
authors.initials: C
authors.lastname: Forcet
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D018797:Cell Cycle Proteins / Q000378:metabolism*; D018833:Chaperonins / Q000378:metabolism*; D004795:Enzyme Stability; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D050883:HSC70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D009097:Multienzyme Complexes; D020033:Protein Isoforms; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D018833:Chaperonins