Cdc37 has distinct roles in protein kinase quality control that protect nascent chains from degradation and promote posttranslational maturation

Mandal, A.; Lee, Paul; Chen, Jennifer A.; Nillegoda, Nadinath B.; Heller, Alana; DiStasio, Susan; Oen, Handy; Victor, Jacob; Nair, Devi M.; Brodsky, Jeffrey L.; Caplan, Avrom J.

doi:10.1083/jcb.200604106

Cited by 93 publications

(96 citation statements)

References 57 publications

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“…Thus, in a setting where the HSP90 system is overworked by the increased concentrations of unstable proteins characteristic of cancer, overexpressed Cdc37 may function by buffering essential kinases in an active state with reduced input from HSP90. Indeed, Cdc37 seems to be especially important for kinase maturation (35). In this study, Mandal et al showed that functional Cdc37 promotes optimal kinase activity for a number of clients without affecting the with an ARE-luciferase reporter plasmid and then grown for 24 h in 10% charcoal-dextran-stripped serum-containing media.…”

Section: Discussionmentioning

confidence: 99%

Targeting Cdc37 Inhibits Multiple Signaling Pathways and Induces Growth Arrest in Prostate Cancer Cells

Gray

Stevenson²,

Calderwood³

2007

Cancer Research

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Members of the 90-kDa heat shock protein (HSP90) family are known to bind and stabilize intermediates in a wide variety of cell signaling pathways and contribute to their dysregulation in cancer. An important intracellular cofactor for HSP90 is Cdc37, a protein with a broad role in fostering the activities of protein kinases. By targeting Cdc37 using RNA interference, we have shown that the loss of Cdc37 function induces irreversible growth arrest in androgen receptor-positive and -negative prostate carcinoma cells. In contrast to HSP90-directed agents, Cdc37 targeting seems to affect cancer cells through a distinct mechanism and does not significantly deplete the intracellular levels of most known HSP90 client proteins. Instead, Cdc37 depletion inhibits cellular kinase activity and flux through growth-promoting signal transduction cascades. We show that the loss of Cdc37 leads to reduced activity of the Erk, Akt, mTOR, and androgen-induced pathways. We have also discovered synergistic interactions between Cdc37 inactivation and the HSP90-inhibitory anticancer drug 17-(allylamino)-17-demethoxygeldanamycin (17AAG). These interactions involve enhanced degradation of proteins essential for growth and inhibition of 17AAG-induced expression of the antiapoptotic HSP70. Thus, Cdc37 is essential for maintaining prostate tumor cell growth and may represent a novel target in the search for multitargeted therapies based on the HSP90 chaperone system. [Cancer Res 2007;67(24):11942-50]

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Section: Discussionmentioning

confidence: 99%

Targeting Cdc37 Inhibits Multiple Signaling Pathways and Induces Growth Arrest in Prostate Cancer Cells

Gray

Stevenson²,

Calderwood³

2007

Cancer Research

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“…In addition, in this genetic background, Hog1 was destabilized during osmotic stress, and the Slt2 activation of downstream targets was decreased. In a screen of the yeast kinome, 75% of kinases were shown to be functionally dependent on Cdc37, demonstrating the breadth and impact of this chaperone (277). Cdc37 is also capable of chaperoning some client protein kinases independently of Hsp90: the kinase-binding domain of Cdc37 is sufficient for cell viability and MAP kinase signaling in sti1⌬ and hsc82⌬ strains that are severely compromised for Hsp90 function (245).…”

Section: The Hsp90 Chaperone Systemmentioning

confidence: 99%

“…In addition, roles of the Hsp70 system, including the Hsp110 NEFs, in mediating client degradation upon misfolding caused by the pharmacological inhibition of transfer to Hsp90 were revealed by using this key reagent (276). A global analysis of the protein and lipid kinase reliance on the Hsp90/Cdc37 system for function demonstrated that a remarkable 51 of 65 kinases examined were destabilized in a cdc37 mutant strain (277). However, to date, the molecular and/or structural determinants that confer kinase reliance on or independence of chaperones have not been elucidated.…”

Section: The Hsp90 Chaperone Systemmentioning

confidence: 99%

Biology of the Heat Shock Response and Protein Chaperones: Budding Yeast (Saccharomyces cerevisiae) as a Model System

Verghese

Abrams

Wang

et al. 2012

Microbiol Mol Biol Rev

503

410

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SUMMARY The eukaryotic heat shock response is an ancient and highly conserved transcriptional program that results in the immediate synthesis of a battery of cytoprotective genes in the presence of thermal and other environmental stresses. Many of these genes encode molecular chaperones, powerful protein remodelers with the capacity to shield, fold, or unfold substrates in a context-dependent manner. The budding yeast Saccharomyces cerevisiae continues to be an invaluable model for driving the discovery of regulatory features of this fundamental stress response. In addition, budding yeast has been an outstanding model system to elucidate the cell biology of protein chaperones and their organization into functional networks. In this review, we evaluate our understanding of the multifaceted response to heat shock. In addition, the chaperone complement of the cytosol is compared to those of mitochondria and the endoplasmic reticulum, organelles with their own unique protein homeostasis milieus. Finally, we examine recent advances in the understanding of the roles of protein chaperones and the heat shock response in pathogenic fungi, which is being accelerated by the wealth of information gained for budding yeast.

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“…Together with its cochaperones, it functions in the conformational control of many regulatory proteins (2)(3)(4). Kinases constitute the largest group of Hsp90 client proteins with more than 60% of the human kinases that depend on Hsp90 in terms of their activity (5,6).…”

mentioning

confidence: 99%

Conformational processing of oncogenic v-Src kinase by the molecular chaperone Hsp90

Boczek

Reefschläger

Dehling

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Hsp90 is a molecular chaperone involved in the activation of numerous client proteins, including many kinases. The most stringent kinase client is the oncogenic kinase v-Src. To elucidate how Hsp90 chaperones kinases, we reconstituted v-Src kinase chaperoning in vitro and show that its activation is ATP-dependent, with the cochaperone Cdc37 increasing the efficiency. Consistent with in vivo results, we find that Hsp90 does not influence the almost identical c-Src kinase. To explain these findings, we designed Src kinase chimeras that gradually transform c-Src into v-Src and show that their Hsp90 dependence correlates with compactness and folding cooperativity. Molecular dynamics simulations and hydrogen/deuterium exchange of Hsp90-dependent Src kinase variants further reveal increased transitions between inactive and active states and exposure of specific kinase regions. Thus, Hsp90 shifts an ensemble of conformations of v-Src toward high activity states that would otherwise be metastable and poorly populated.Cdc37 | kinase activation | metastable states | conformational ensembles | chaperone mechanism

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Cdc37 has distinct roles in protein kinase quality control that protect nascent chains from degradation and promote posttranslational maturation

Cited by 93 publications

References 57 publications

Targeting Cdc37 Inhibits Multiple Signaling Pathways and Induces Growth Arrest in Prostate Cancer Cells

Targeting Cdc37 Inhibits Multiple Signaling Pathways and Induces Growth Arrest in Prostate Cancer Cells

Biology of the Heat Shock Response and Protein Chaperones: Budding Yeast (Saccharomyces cerevisiae) as a Model System

Conformational processing of oncogenic v-Src kinase by the molecular chaperone Hsp90

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