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

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. Oncogene (2003) 22, 9165-9175.

STE20-related Kinase Adaptor Protein α (STRADα) Regulates Cell Polarity and Invasion through PAK1 Signaling in LKB1-null Cells

“…In LKB1 wild-type cells, STRAD␣ is degraded through the proteasome in an Hsp90-dependent manner but turnover is enhanced when LKB1 is mutant. This pathway is similar to the LKB1 degradation pathway where LKB1 interacts with the molecular chaperones Hsp90 and Cdc37/p50 to regulate LKB1 stability and proteasomal degradation (42,43). Based upon our data, we propose a model that when LKB1 is present, STRAD␣ is degraded via the proteasome in an Hsp90-dependent manner but when LKB1 is mutant or absent, the rate of STRAD␣ degradation through this pathway is increased.…”

Interaction with 14-3-3 Adaptors Regulates the Sorting of hMex-3B RNA-binding Protein to Distinct Classes of RNA Granules

“…Protein Analyses and Immunoprecipitation-Cells were lysed 48 h post-transfection, and Western blot analyses and immunoprecipitations were performed as described earlier (14,23) (see supplemental "Materials and Methods"). Quantitative Western blot analyses were performed using Li-Cor Odissey (Li-Cor Biosciences) according to the manufacturer's instruction (see supplemental "Materials and Methods").…”

Molecular chaperone complexes with antagonizing activities regulate stability and activity of the tumor suppressor LKB1

“…The chaperone Hsp90 interacts with and stabilizes LKB1 (Nony et al, 2003;Boudeau et al, 2003a). We and others have shown that cell treatment with geldanamycin (GA), an Hsp90-specific inhibitor, induces the proteasomemediated degradation of LKB1.…”

“…We and others have shown that cell treatment with geldanamycin (GA), an Hsp90-specific inhibitor, induces the proteasomemediated degradation of LKB1. It was also reported that the co-chaperone adaptator Cdc37 binds to LKB1 (Nony et al, 2003;Boudeau et al, 2003a). However, whether this interaction is involved in the control of LKB1 protein stability was not determined.…”

“…In this line, we and others have previously reported that the stability of LKB1 depends on its binding to Hsp90 (Nony et al, 2003;Boudeau et al, 2003a). We subsequently decided to explore further the molecular mechanisms regulating LKB1 stabilization, and characterize the factors involved in its degradation.…”