# Regulatory mechanisms of the Hsp90 chaperone machinery

> **NIH NIH R35** · UPSTATE MEDICAL UNIVERSITY · 2022 · $404,524

## Abstract

PROJECT SUMMARY
The molecular chaperone Heat Shock Protein-90 (Hsp90) is essential for the folding and
activity of an array of `client' proteins involved in signal transduction pathways. They are
also responsible for many maladies including cancer, neurodegenerative, autoimmune
and inflammatory diseases. Hsp90 inhibition strategies are currently being explored in
these diseases in pre-clinical studies and clinical trials, however the optimal use of
Hsp90-targeted therapeutics remains unknown. This is partly due to our limited
knowledge of Hsp90 regulation in cells. Unraveling the detailed regulatory mechanisms
of Hsp90 function in cells can provide new strategies to increase the cellular potency of
Hsp90 inhibitors. Hsp90 chaperone function is coupled to its ATPase activity, which is
regulated by co-chaperones and posttranslational modifications (PTMs). However, it is
unclear how these regulatory components work together to fine tune Hsp90 function and
also contribute towards drug sensitivity. During the past five years we have made major
contributions towards the understanding of Hsp90 regulation by co-chaperones and
PTMs. i) New co-chaperones: We have identified three new co-chaperones, FNIP1, 2
(collectively FNIPs) and Tsc1, that decelerate the chaperone cycle and facilitate chaper-
oning of both kinase and non-kinase clients. They are regulated by PTMs (phosphoryla-
tion, O-GlcNAcylation, SUMOlyation and ubiquitination). Their expression also enhances
Hsp90 binding to drugs and consequently sensitizes cells to Hsp90 inhibitors. ii) Post-
translational modification of Hsp90: Our work during the past decade on Hsp90 PTMs
has redefined the regulation of its chaperone activity and revealed the reciprocal regula-
tory mechanisms between client proteins, co-chaperones, and Hsp90. We have recently
shown that loss of TSC1 co-chaperone leads to hypoacetylation of Hsp90 and elevated
its ATPase activity. It also subsequently decreased Hsp90 binding to its inhibitors. Our
long-term goal is to unravel the molecular mechanism of Hsp90 chaperone regulation in
cells and regulatory factors enhancing cellular potency of Hsp90 inhibitors. Our strategy
is to use biochemical, biophysical and cell-based assays to decipher the interconnectivi-
ty and compensatory mechanisms between the co-chaperones and PTMs. Our vision is
to utilize this information to dissect the intricate network of regulatory signals involved in
fine tuning Hsp90 function and their impact towards cellular sensitivity to Hsp90 inhibi-
tors.

## Key facts

- **NIH application ID:** 10319559
- **Project number:** 5R35GM139584-02
- **Recipient organization:** UPSTATE MEDICAL UNIVERSITY
- **Principal Investigator:** Mehdi Mollapour
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $404,524
- **Award type:** 5
- **Project period:** 2021-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10319559

## Citation

> US National Institutes of Health, RePORTER application 10319559, Regulatory mechanisms of the Hsp90 chaperone machinery (5R35GM139584-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10319559. Licensed CC0.

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