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Mechanisms of Phosphorylation Signaling by Phosphoprotein Phosphatases

Award Number: R35GM119455
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/05/2016
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Mechanisms of Phosphorylation Signaling by Phosphoprotein Phosphatases - Abstract Reversible protein phosphorylation is a major regulatory mechanism that controls most cellular processes, including mitosis. A ‘tug of war’ between kinases and phosphatases controls protein activity and function. The precise coordination of both activities is essential for the accurate execution of cell division. Despite substantial progress in deciphering kinase-mediated phosphorylation and its functional consequences, much less is known about phosphatases and how dephosphorylation is regulated. The long-term goal of our research program is to uncover the mechanisms that coordinate and integrate PPPs, kinases, and their shared substrates in the signaling networks that control cell division. The majority of cellular dephosphorylation is carried out by the 7 catalytic phosphatase subunits of the phosphoprotein phosphatase (PPP) family. Despite the apparent simplicity suggested by the small number of catalytic PPP enzymes, complexity and specificity arise through the formation of holoenzymes. Each holoenzyme functions as a distinct entity. The non-catalytic subunits modulate the activity of the catalytic subunits, enabling substrate specificity, dictating subcellular localization, and ensuring appropriate regulation. Combinatorially, there are several hundred functional PPP holoenzymes. There are key gaps in knowledge and challenges in studying PPP function and mechanisms of dephosphorylation. Although hundreds of thousands of phosphorylated sites on proteins have been identified, only ~450 have been matched to be dephosphorylated by a specific PPP holoenzyme. This is in part due to the lack of holoenzyme-specific inhibitors and the complexity of PPP holoenzymes. To overcome these obstacles and fill these gaps in knowledge, we will (i) identify holoenzyme-specific substrates; (ii) dissect mechanisms of substrate recruitment and site-specific dephosphorylation; and (iii) determine regulatory inputs governing specific PPP holoenzymes. We have developed new cell biological and biochemical approaches to investigate PPP signaling. We plan to map the PPP substrate space comprehensively, providing a foundation for studying PPPs for our lab and the signaling community by sharing our findings broadly and openly via a user-friendly database that we will maintain. The mechanisms that PPPs use to recruit substrates and catalyze site-specific dephosphorylation are still emerging. We will continue to dissect these mechanisms to predict and systematically dissect PPP-substrate relationships in cells. Finally, determining regulatory inputs that govern PPP holoenzyme formation, activity, and function is needed to understand their role in regulating mitosis. We combine quantitative measurements of the proteome and phosphoproteome with the reconstitution of minimal signaling units in vitro and in cells to precisely determine phosphatase function and regulation in cell division.


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: 2025 ( Subtotal = $442,800 )
2025	2025	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Biomedical Research and Research Training	001	10	5/19/2025	NON-COMPETING CONTINUATION	$442,800
2025	2024	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Biomedical Research and Research Training	000	9	11/18/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $442,800

Issue Date FY: 2024 ( Subtotal = $442,800 )
2024	2024	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Biomedical Research and Research Training	000	9	5/15/2024	NON-COMPETING CONTINUATION	$442,800
														Subtotal = $442,800

Issue Date FY: 2023 ( Subtotal = $442,800 )
2023	2023	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Biomedical Research and Research Training	000	8	5/15/2023	NON-COMPETING CONTINUATION	$442,800
														Subtotal = $442,800

Issue Date FY: 2022 ( Subtotal = $442,800 )
2022	2022	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Biomedical Research and Research Training	002	7	5/23/2022	NON-COMPETING CONTINUATION	$442,800
2022	2021	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Biomedical Research and Research Training	001	6	11/6/2021	COMPETING CONTINUATION	$9,945
2022	2020	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Biomedical Research and Research Training	000	5	11/6/2021	NON-COMPETING CONTINUATION	-$9,945
														Subtotal = $442,800

Issue Date FY: 2021 ( Subtotal = $536,869 )
2021	2021	TRUSTEES OF DARTMOUTH COLLEGE	6001 PARKHURST HALL STE 207	HANOVER	NH	03755	GRAFTON	USA	Biomedical Research and Research Training	001	6	8/12/2021	SUPPLEMENT FOR EXPANSION	$94,069
2021	2021	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Biomedical Research and Research Training	000	6	4/27/2021	COMPETING CONTINUATION	$442,800
														Subtotal = $536,869

Issue Date FY: 2020 ( Subtotal = $404,998 )
2020	2020	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Biomedical Research and Research Training	000	5	5/14/2020	NON-COMPETING CONTINUATION	$404,998
														Subtotal = $404,998

Issue Date FY: 2019 ( Subtotal = $402,768 )
2019	2019	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Biomedical Research and Research Training	000	4	5/21/2019	NON-COMPETING CONTINUATION	$402,768
														Subtotal = $402,768

Issue Date FY: 2018 ( Subtotal = $603,406 )
2018	2018	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Biomedical Research and Research Training	000	3	5/21/2018	NON-COMPETING CONTINUATION	$403,406
2018	2018	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Biomedical Research and Research Training	001	3	9/3/2018	SUPPLEMENT FOR EXPANSION	$200,000
														Subtotal = $603,406

Issue Date FY: 2017 ( Subtotal = $404,418 )
2017	2017	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Biomedical Research and Research Training	000	2	5/25/2017	NON-COMPETING CONTINUATION	$404,418
														Subtotal = $404,418

Issue Date FY: 2016 ( Subtotal = $346,605 )
2016	2016	DARTMOUTH COLLEGE	11 ROPE FERRY ROAD, #6210	HANOVER	NH	03755	GRAFTON	USA	Biomedical Research and Research Training	000	1	8/5/2016	NEW	$346,605
														Subtotal = $346,605

Grand Total All Awards = $4,470,264

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Mechanisms of Phosphorylation Signaling by Phosphoprotein Phosphatases

Award Number: R35GM119455

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/05/2016

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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