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Specific regulation of noncanonical p38alpha activation by Hsp90-Cdc37 chaperone complex in cardiomyocyte.

ABSTRACT: p38 is an important stress activated protein kinase involved in gene regulation, proliferation, differentiation, and cell death regulation in heart. p38 kinase activity can be induced through canonical pathway via upstream kinases or by noncanonical autophosphorylation. The intracellular p38 kinase activity is tightly regulated and maintained at low level under basal condition. The underlying regulatory mechanism for canonical p38 kinase activation is well-studied, but the regulation of noncanonical p38 autophosphorylation remains poorly understood.We investigated the molecular basis for the regulation of noncanonical p38 autophosphorylation and its potential functional impact in cardiomyocytes.Using both proteomic and biochemical tools, we established that heat shock protein (Hsp)90-Cdc37 chaperones are part of the p38alpha signaling complex in mammalian cells both in vitro and in vivo. The Hsp90-Cdc37 chaperone complex interacts with p38 via direct binding between p38 and Cdc37. Cdc37 expression is both sufficient and necessary to suppress noncanonical p38 activation via autophosphorylation at either basal state or under TAB1 (TAK1 binding protein-1) induction. In contrast, Cdc37 expression has no impact on p38 activation by canonical upstream kinase MKK3 or oxidative stress. Furthermore, Hsp90 inhibition results in p38 activation via autophosphorylation, and p38 activity contribute to apoptotic cell death induced by Hsp90 inhibition.Our study has revealed a so far uncharacterized function of Hsp90-Cdc37 as an endogenous regulator of noncanonical p38 activity.

SUBMITTER: Ota A

PROVIDER: S-EPMC2891038 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Specific regulation of noncanonical p38alpha activation by Hsp90-Cdc37 chaperone complex in cardiomyocyte.

Ota Asuka A Zhang Jun J Ping Peipei P Han Jiahuai J Wang Yibin Y

Circulation research 20100318 8

<h4>Rationale</h4>p38 is an important stress activated protein kinase involved in gene regulation, proliferation, differentiation, and cell death regulation in heart. p38 kinase activity can be induced through canonical pathway via upstream kinases or by noncanonical autophosphorylation. The intracellular p38 kinase activity is tightly regulated and maintained at low level under basal condition. The underlying regulatory mechanism for canonical p38 kinase activation is well-studied, but the regu ...[more]

PMID: 20299663

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Project description:BackgroundHSPs (Heat shock proteins) are highly conserved ubiquitous proteins among species which are involved in maintaining appropriate folding and conformation of other proteins and are thus referred to as molecular chaperones. Hsp90 (Heat-shock protein 90 kDa) is one of a group of molecular chaperones responsible for managing protein folding and quality control in cell environment. However it is also involved in the maturation and stabilization of a wide range of oncogenic client proteins which are crucial for oncogenesis and malignant progression. Hsp90 requires a series of co-chaperones to assemble into a super-chaperone complex for its function. These co-chaperones bind and leave the complex at various stages to regulate the chaperoning process. Arresting the chaperone cycle at these stages by targeting different co-chaperone/Hsp90 interactions seems to be quite a viable alternative and is likely to achieve similar consequences as that of Hsp90 direct inhibition with added favors of high specificity and reduced side effect profile. The study conducted here is an attempt to explore the potential of Withania somnifera's major constituent WA (Withaferin A) in attenuating the Hsp90/Cdc37 chaperone/co-chaperone interactions for enhanced tumor arresting activity and to elucidate the underlying mode of action using computational approaches.ResultsFormation of active Hsp90/Cdc37 complex is one of the essential steps for facilitation of chaperone client interaction, non-assembly of which can lead to prevention of the chaperone-client association resulting in apoptosis of tumor cells. From our flexible docking analysis of WA into active Hsp90/Cdc37 complex in which key interfacing residues of the complex were kept flexible, disruption of the active association complex can be discerned. While docking of WA into segregated Hsp90 leaves the interface residues untouched. Thus the molecular docking analysis of WA into Hsp90 and active Hsp90/Cdc37 complex conducted in this study provides significant evidence in support of the proposed mechanism of chaperone assembly suppression by inhibition or disruption of active Hsp90/Cdc37 complex formation being accounted by non-assembly of the catalytically active Hsp90/Cdc37 complex. Results from the molecular dynamics simulations in water show that the trajectories of the protein complexed with ligand WA are stable over a considerably long time period of 4 ns, with the energies of the complex being lowered in comparison to the un-docked association complex, suggesting the thermodynamic stability of WA complexed Hsp90/Cdc37.ConclusionsThe molecular chaperone Hsp90 has been a promising target for cancer therapy. Cancer is a disease marked by genetic instability. Thus specific inhibition of individual proteins or signalling pathways holds a great potential for subversion of this genetic plasticity of cancers. This study is a step forward in this direction. Our computational analysis provided a rationalization to the ability of naturally occurring WA to alter the chaperone signalling pathway. The large value of binding energy involved in binding of WA to the active Hsp90/Cdc37 complex consolidates the thermodynamic stability of the binding. Our docking results obtained substantiate the hypothesis that WA has the potential to inhibit the association of chaperone (Hsp90) to its co-chaperone (Cdc37) by disrupting the stability of attachment of Hsp90 to Cdc37. Conclusively our results strongly suggest that withaferin A is a potent anticancer agent as ascertained by its potent Hsp90-client modulating capability.

Dataset Information

Specific regulation of noncanonical p38alpha activation by Hsp90-Cdc37 chaperone complex in cardiomyocyte.

Publications

Specific regulation of noncanonical p38alpha activation by Hsp90-Cdc37 chaperone complex in cardiomyocyte.

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