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Crosstalk between post-translational regulations of the FNIP co-chaperones and their impact on Hsp90 chaperone function and drug binding

Award Number: R01GM124256
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY The molecular chaperone Heat Shock Protein-90 (Hsp90) is considered to be a critical facilitator of oncogene addiction and cancer cell survival. Hsp90 function is coupled to its ATPase activity, which is regulated by co-chaperones and posttranslational modifica- tions (PTMs). Hsp90 inhibitors are currently being evaluated in various stages of clinical trials in cancer patients. However, the optimal use of Hsp90-targeted therapy remains unknown. This is partly due to the limited knowledge of Hsp90 regulation in cancer cells. Folliculin-interacting proteins (FNIP-1 and 2), also known as FNIPs, are the newly dis- covered co-chaperones that decelerate Hsp90 activity. FNIPs compete with the activat- ing co-chaperone Aha1 for binding to Hsp90 and FNIPs expression correlates with the cellular response to Hsp90 inhibitors. It was also shown that PTMs (phosphorylation, O- GlcNAcylation, ubiquitination) of FNIPs and Aha1 affect their binding to Hap90, however, the detailed crosstalk between these PTMs and their impact on drug sensitivity remains unknown. Without this knowledge, optimal Hsp90-targeted therapeutics remains limited. The long-term goal of this proposal is to enhance the activity of the Hsp90 inhibitors in cancer cells by targeting the regulators of Hsp90. The overall objective is to determine the crosstalk between PTMs of co-chaperones in regulating Hsp90 function and how they contribute towards drug sensitivity. The central hypothesis is that PTMs of the FNIPs and Aha1 co-chaperones reciprocally impact their binding to Hsp90 and influence the potency of its drugs in cancer cells. The rationale of this proposal is that, by under- standing the impact of PTMs on co-chaperones association with Hsp90 and consequent- ly drug binding, it could be possible to target those enzymes responsible for the PTMs, therefore increasing the potency of Hsp90 inhibitors in cancer cells. Biochemical, bio- physical and cell-based assays as well as cancer cell lines will be used to test the hy- pothesis in the following specific aims; Aim 1: Determine the impact of crosstalk between phosphorylation and O-GlcNAcylation on co-chaperone activity of the FNIPs. Aim 2: De- termine the reciprocal role of FNIP1 and Aha1 co-chaperones on Hsp90 regulation. Aim 3: Determine the mechanism of FNIP co-chaperones on increasing the activity of Hsp90 inhibitors. In determining the interplay between FNIPs and Aha1 co-chaperones and how PTMs of these two proteins impact their binding to Hsp90, it is expected to unravel new targets to increase the potency of Hsp90 inhibitors in cancer cells.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Biomedical Research and Research Training	000	4	10/27/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $311,850 )
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Biomedical Research and Research Training	000	4	3/13/2020	NON-COMPETING CONTINUATION	$311,850
														Subtotal = $311,850

Issue Date FY: 2019 ( Subtotal = $311,850 )
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Biomedical Research and Research Training	000	3	3/26/2019	NON-COMPETING CONTINUATION	$311,850
														Subtotal = $311,850

Issue Date FY: 2018 ( Subtotal = $371,850 )
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Biomedical Research and Research Training	002	2	9/12/2018	SUPPLEMENT FOR EXPANSION	$60,000
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Biomedical Research and Research Training	001	2	5/30/2018	NON-COMPETING CONTINUATION	$31,185
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Biomedical Research and Research Training	000	2	3/15/2018	NON-COMPETING CONTINUATION	$280,665
														Subtotal = $371,850

Issue Date FY: 2017 ( Subtotal = $311,850 )
2017	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Biomedical Research and Research Training	000	1	7/5/2017	NEW	$311,850
														Subtotal = $311,850

Grand Total All Awards = $1,307,400

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Crosstalk between post-translational regulations of the FNIP co-chaperones and their impact on Hsp90 chaperone function and drug binding

Award Number: R01GM124256

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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