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Studying the ERK phosphorylation of the BCAT protein

Award Number: SC2GM139698
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: 05/01/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2024

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Studying the ERK phosphorylation of the BCAT protein - The cytosolic and mitochondrial isoforms of human branched chain aminotransferase (hBCATc and hBCATm, respectively) catalyze the transamination of the branched chain amino acids (BCAA) to their respective α-keto acids and glutamate. In addition, we recently found that hBCAT is phosphorylated by the canonical mitogen- activated protein kinase (MAPK) family member, extracellular regulated kinase 1/2 (ERK1/2). Our research team has shown direct evidence that ERK1/2 protein interacts with hBCATc in vitro and in breast cancer cells. More specifically, we found in breast cancer cells the overexpression of BCAT1 (gene encoding hBCATc) resulted in decreased levels of ERK1/2 activation/phosphorylation, and our in vitro experiments showed activated/phosphorylated ERK1/2 phosphorylates hBCATc regulated by the redox center of hBCAT. Together, the physiological implications of these observations are considerable to better understand the cellular and molecular mechanisms of how hBCATc interacts with ERK1/2. In this proposal we will focus on the protein- protein interaction of ERK1/2-mediated phosphorylation of the hBCATc. Based on preliminary studies, we hypothesize that the redox center regulated phosphorylation of hBCATc by ERK1/2 signals this metabolic protein to play additional functional roles in the cell, with the redox center of hBCAT playing an important role in protein-protein interactions between hBCAT and ERK1/2. We hypothesize that hBCAT is differentially phosphorylated by various kinases, which causes a conformational change of hBCAT that potentially confers p-hBCAT with new functions. In the proposed project, we will study the regulatory effects of phosphorylation of hBCAT by ERK1/2 using complementary biochemical and biophysical strategies, including kinetics analysis, mass spectrometry and X-ray crystallography. Likewise, redox regulation of ERK1/2 is also a theme to be developed in this project. Together, these experiments are expected to provide a comprehensive basis for understanding the mechanism of the redox-regulated phosphorylation of BCAT by ERK1/2, and the structural effects of phosphorylation on hBCAT. Moreover, these studies will establish a workflow to examine various hBCAT-kinase interactions and help us further study the phosphorylation-mediated conformational changes of hBCAT by other kinases that will help us to better understand the functional consequences of intracellular phosphorylation of hBCAT. This project will provide for the first-time unique insights into the molecular mechanisms underlying the redox regulation of hBCAT-ERK1/2 interactions, which will fundamentally inform its role in disease conditions such as breast cancer and Alzheimer’s 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: 2025 ( Subtotal = -$203,971 )
2025	2023	NORTH CAROLINA AGRICULTURAL AND TECHNICAL STATE UNIVERSITY	1601 E MARKET ST	GREENSBORO	NC	27411	GUILFORD	USA	Biomedical Research and Research Training	001	3	10/29/2024	NON-COMPETING CONTINUATION	-$141,140
2025	2022	NORTH CAROLINA AGRICULTURAL AND TECHNICAL STATE UNIVERSITY	1601 E MARKET ST	GREENSBORO	NC	27411	GUILFORD	USA	Biomedical Research and Research Training	000	2	10/29/2024	NON-COMPETING CONTINUATION	-$62,831
														Subtotal = -$203,971

Issue Date FY: 2023 ( Subtotal = $141,140 )
2023	2023	NORTH CAROLINA AGRICULTURAL AND TECHNICAL STATE UNIVERSITY	1601 E MARKET ST	GREENSBORO	NC	27411	GUILFORD	USA	Biomedical Research and Research Training	000	3	4/10/2023	NON-COMPETING CONTINUATION	$141,140
														Subtotal = $141,140

Issue Date FY: 2022 ( Subtotal = $141,140 )
2022	2022	NORTH CAROLINA AGRICULTURAL AND TECHNICAL STATE UNIVERSITY	1601 E MARKET ST DOWDY BLDG STE 418 221 DOWDY ADM BLDG	GREENSBORO	NC	27411	GUILFORD	USA	Biomedical Research and Research Training	000	2	4/27/2022	NON-COMPETING CONTINUATION	$141,140
														Subtotal = $141,140

Issue Date FY: 2021 ( Subtotal = $137,400 )
2021	2021	NORTH CAROLINA AGRICULTURAL AND TECHNICAL STATE UNIVERSITY	1601 E MARKET ST DOWDY BLDG STE 418 221 DOWDY ADM BLDG	GREENSBORO	NC	27411	GUILFORD	USA	Biomedical Research and Research Training	000	1	4/21/2021	NEW	$137,400
														Subtotal = $137,400

Grand Total All Awards = $215,709

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Studying the ERK phosphorylation of the BCAT protein

Award Number: SC2GM139698

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: 05/01/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2024

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