The CDC37‐HSP90 chaperone complex co‐translationally degrades the nascent kinase‐dead mutant of HIPK2

Müller, Jan Paul; Klempnauer, Karl‐Heinz

doi:10.1002/1873-3468.14080

Cited by 6 publications

(4 citation statements)

References 47 publications

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“…Although client binding by HSP90 is thought to be posttranslational, some studies have reported that kinases undergo co‐translational degradation when the chaperone is inhibited (Müller et al, 2021 ; Müller & Klempnauer, 2021 ). We found that blocking translation with cycloheximide prior to HSP90 inhibition did not reduce the degradation of either c‐Src KD or Lck KD , suggesting that HSP90‐stabilization of c‐Src KD and Lck KD does not depend on active synthesis of the clients (Figure S4B ).…”

Section: Resultsmentioning

confidence: 99%

A fluorescence‐based sensor for calibrated measurement of protein kinase stability in live cells

Paul,

Muratcioğlu,

Kuriyan

2024

Protein Science

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Oncogenic mutations can destabilize signaling proteins, resulting in increased or unregulated activity. Thus, there is considerable interest in mapping the relationship between mutations and the stability of signaling proteins, to better understand the consequences of oncogenic mutations and potentially inform the development of new therapeutics. Here, we develop a tool to study protein‐kinase stability in live mammalian cells and the effects of the HSP90 chaperone system on the stability of these kinases. We determine the expression levels of protein kinases by monitoring the fluorescence of fluorescent proteins fused to those kinases, normalized to that of co‐expressed reference fluorescent proteins. We used this tool to study the dependence of Src‐ and Raf‐family kinases on the HSP90 system. We demonstrate that this sensor reports on destabilization induced by oncogenic mutations in these kinases. We also show that Src‐homology 2 and Src‐homology 3 domains, which are required for autoinhibition of Src‐family kinases, stabilize these kinase domains in the cell. Our expression‐calibrated sensor enables the facile characterization of the effects of mutations and small‐molecule drugs on protein‐kinase stability.

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Section: Resultsmentioning

confidence: 99%

A fluorescence‐based sensor for calibrated measurement of protein kinase stability in live cells

Paul,

Muratcioğlu,

Kuriyan

2024

Protein Science

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“…Although client binding by HSP90 is thought to be post-translational, some studies have reported that kinases undergo co-translational degradation when the chaperone is inhibited 61,62 . We found that blocking translation with cycloheximide prior to HSP90 inhibition did not reduce the degradation of either c-Src KD or Lck KD , suggesting that HSP90-stabilization of c-Src KD and Lck KD from degradation occurs primarily after translation (figure S4B).…”

Section: Resultsmentioning

confidence: 99%

A Fluorescence-Based Sensor for Calibrated Measurement of Protein Kinase Stability in Live Cells

Paul,

Muratcioğlu,

Kuriyan

2023

Preprint

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Oncogenic mutations can destabilize signaling proteins, resulting in increased or unregulated activity. Thus, there is considerable interest in mapping the relationship between mutations and the stability of proteins, to better understand the consequences of oncogenic mutations and potentially inform the development of new therapeutics. Here, we develop a tool to study protein-kinase stability in live mammalian cells and the effects of the HSP90 chaperone system on the stability of these kinases. We monitor the fluorescence of kinases fused to a fluorescent protein relative to that of a co-expressed reference fluorescent protein. We used this tool to study the dependence of Src- and Raf-family kinases on the HSP90 system. We demonstrate that this sensor reports on destabilization induced by oncogenic mutations in these kinases. We also show that Src-homology 2 (SH2) and Src-homology 3 (SH3) domains, which are required for autoinhibition of Src-family kinases, stabilize these kinase domains in the cell. Our expression-calibrated sensor enables the facile characterization of the effects of mutations and small-molecule drugs on protein-kinase stability.

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“…CDC37 is barely expressed in normal prostate tissue, with the highest proportion of CDC37-positive cells in moderately differentiated prostate cancer, and has been confirmed to be a HSP90 kinase-specific partner. Specific inhibition of HSP90 kinase can be achieved by blocking its interaction or directly inhibiting CDC37, and the development of small molecule inhibitors targeting HSP90-CDC37 is another effective strategy for implementing cancer treatment ( 28 , 29 ). Our data showed that miR-885-5p can affect cell proliferation by inhibiting CDC37.…”

Section: Discussionmentioning

confidence: 99%

Arsenic Trioxide Affects the Proliferation of Gastric Cancer Cells through MiR-885-5p/CDC73 Axis

Guo¹,

Zhu²

2023

ijph

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Background: To explore Arsenic trioxide (As2O3) and its regulated miR-885-5p/CDC73 signaling pathway involved in the development of gastric cancer. Methods: Fifty-two healthy patients and patients with gastric cancer were enrolled 2019-2020 in He Xian Memorial Hospital, Guangzhou, China. The patients with gastric cancer were divided into control group and As2O3 administration group. After 2 courses of treatment, their peripheral blood was collected to analyze the therapeutic effect. miR-885-5p expression in peripheral blood was analyzed by qRT-PCR. As2O3 was added into MGC-803 gastric cancer cell line at 0, 10, 20, 40 and 80 μmol/L. The proliferation rate and 48h IC50 value of gastric cancer cells were investigated by CCK-8, and the effect of As2O3 on miR-885-5p expression in the cells was analyzed. Results: After 4 weeks of treatment, the objective efficiency of control group and As2O3 administration group was 17.3% and 13.4%, respectively, without significant statistical difference. The overall benefit rate of As2O3 administration group was significantly higher than that of the normal treatment group (P=0.049). qRT-PCR experiment results found that miR-885-5p significantly highly expressed in peripheral blood in the As2O3 administration group, while miR-885-5p in gastric cancer was lower compared with normal people. Adding As2O3 to the gastric cancer cells could significantly inhibit miR-885-5p expression, while miR-885-5p in gastric cancer cells affected cell expression by targeted regulation, affecting cell proliferation. Conclusion: As2O3 may be used as a drug treatment program for gastric cancer, and mainly regulates the proliferation of gastric cancer cells by affecting the miR-885-5p/CDC73 target axis to participate in the development of gastric cancer.

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The CDC37‐HSP90 chaperone complex co‐translationally degrades the nascent kinase‐dead mutant of HIPK2

Cited by 6 publications

References 47 publications

A fluorescence‐based sensor for calibrated measurement of protein kinase stability in live cells

A fluorescence‐based sensor for calibrated measurement of protein kinase stability in live cells

A Fluorescence-Based Sensor for Calibrated Measurement of Protein Kinase Stability in Live Cells

Arsenic Trioxide Affects the Proliferation of Gastric Cancer Cells through MiR-885-5p/CDC73 Axis

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