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Regulation of cell growth and proliferation by the Hippo pathway

Award Number: R01GM117150
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: 09/23/2016
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Regulation of cell growth and proliferation by the Hippo pathway - PROJECT SUMMARY/ABSTRACT Precise regulation of cell growth and proliferation is necessary to maintain tissue homeostasis and organ size, and this regulation is predominantly controlled by two highly conserved signaling pathways: the Hippo and mammalian target of rapamycin (mTOR) pathways. Deregulation of the Hippo and/or mTOR pathways cause tissue overgrowth phenotypes that are well known to contribute to human disease. Understanding how the Hippo and mTOR signaling pathways coordinate their activities is therefore a critically important, yet poorly understood, area of cell biology. In the last funding period, my group identified the kinase STK25 as an upstream activator of the Hippo signaling pathway that directly phosphorylates and activates the core Hippo kinases LATS1 and LATS2 to induce cell cycle arrest. We have now generated strong preliminary data indicating that activation of STK25 also functions to dampen mTORC1 signaling, both in vitro and in vivo. However, the mechanism by which STK25 regulates mTORC1 is unknown. The goal of this proposal is to combine cell biology, biochemistry, CRISPR-screening, and animal model methodologies to test our overarching hypothesis that the kinase activity of STK25 plays a critical role in coordinating the activities of both the Hippo and mTORC1 signaling pathways to regulate cell growth and tissue homeostasis. In Aim 1, we will use unbiased chemical-genetic and phospho- proteomic approaches to identify STK25 substrates and define the molecular mechanisms through which STK25 negatively regulates mTORC1 activity. In Aim 2, we will define how STK25 kinase activity is regulated, and use a conditional STK25 knockout mouse model we have recently developed to determine the phenotypic consequences of STK25 gene deletion on cell growth and proliferation in vivo. In Aim 3, we will use an innovative gain-of-function CRISPRa-based screen to identify new regulators of the Hippo pathway, both in vitro and in vivo. Successful completion of these aims will illuminate fundamental principles as to how the Hippo and mTORC1 signaling pathways coordinate their activities to maintain tissue homeostasis and provide new insights into how these pathways are deregulated in human disease.


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: 2026 ( Subtotal = $386,685 )
2026	2026	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	000	7	2/27/2026	NON-COMPETING CONTINUATION	$386,685
														Subtotal = $386,685

Issue Date FY: 2025 ( Subtotal = $386,685 )
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	000	6	12/18/2024	COMPETING CONTINUATION	$386,685
														Subtotal = $386,685

Issue Date FY: 2023 ( Subtotal = -$3,868 )
2023	2020	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	000	5	1/6/2023	NON-COMPETING CONTINUATION	-$3,868
														Subtotal = -$3,868

Issue Date FY: 2020 ( Subtotal = $330,000 )
2020	2020	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	000	5	6/16/2020	NON-COMPETING CONTINUATION	$330,000
														Subtotal = $330,000

Issue Date FY: 2019 ( Subtotal = $330,000 )
2019	2019	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	000	4	6/28/2019	NON-COMPETING CONTINUATION	$330,000
														Subtotal = $330,000

Issue Date FY: 2018 ( Subtotal = $330,000 )
2018	2018	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	000	3	7/10/2018	NON-COMPETING CONTINUATION	$330,000
														Subtotal = $330,000

Issue Date FY: 2017 ( Subtotal = $329,000 )
2017	2017	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	000	2	6/28/2017	NON-COMPETING CONTINUATION	$329,000
														Subtotal = $329,000

Issue Date FY: 2016 ( Subtotal = $329,000 )
2016	2016	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	000	1	9/23/2016	NEW	$329,000
														Subtotal = $329,000

Grand Total All Awards = $2,417,502

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Regulation of cell growth and proliferation by the Hippo pathway

Award Number: R01GM117150

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: 09/23/2016

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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