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Role of Phosphorylation in RNA Binding Protein Function

Award Number: SC3GM132036
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: 04/01/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2024

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Role of Phosphorylation in RNA Binding Protein Function - Project Summary Many RNA binding proteins (RBPs) that regulate alternative pre-mRNA splicing occur as gene families with members sharing high primary and tertiary structural similarity. Yet these paralogs have non-overlapping tissue- specific expression patterns and regulate over-lapping and distinct sets of target exons to elicit tissue-specific splicing programs. How these paralogs achieve tissue-specific splicing patterns is not understood, and if known, would facilitate the manipulation of gene expression to treat tissue-specific splicing related diseases. In this project, we propose to investigate the role of post-translational phosphorylation in the tissue-specific splicing activities of polypyrimidine tract binding proteins PTBP1 and PTPB2. The amino acid sequence of PTBP2 is 74% identical to that of PTBP1. The two proteins share a similar domain organization, recognize and bind to the same sequence elements in adjacent target exons and most often function as splicing repressors. However, PTBP1 and PTBP2 have distinct expression patterns that play a critical role in neuronal development and maturation. Neuronal progenitor cells express PTBP1, but during differentiation the level of PTBP1 is down-regulated, and that of PTBP2 is up-regulated. These changes in PTBP protein expression alter the splicing of a set of neuronal exons leading to changes in many transcripts that code for proteins critical for development of axons, dendrites and the formation of synapses. Thus, changes in PTPB1 and PTPB2 expression clearly alter (and thus regulate) the patterns of splicing required for neuronal development. However, how these paralogs elicit these distinct splicing outcomes is completely unknown. We recently discovered that PTBP1 and PTBP2 are post- translationally phosphorylated under splicing conditions. PTBP2 has many more non-overlapping distinct sites of phosphorylation than PTBP1 and these sites are localized to the unstructured N-terminal and linker regions, which share less sequence identity than their RNA binding domains. Moreover, PTBP2 distinct phosphorylated residues are not conserved in PTBP1, yet are maintained in lower species than humans implying they were acquired/lost after gene duplication and that they may play a role in PTBP2 splicing activity. These findings suggest that reversible phosphorylation might dictate the tissue-specific splicing activities of PTBP1 and PTBP2. Our specific aims are to test this hypothesis. Aim 1: Determine the role of phosphorylation in PTBP2 RNA binding activity Aim 2: Determine the role of linker regions and phosphorylation in PTBP2 splicing regulation Aim 3: Determine cell signaling pathways involved in PTBP2 neuronal splicing regulation Our studies would answer fundamentally important questions about how structurally related paralogous proteins dictate different splicing outcomes and also reveal how the neuronal splicing program is modulated via reversible phosphorylation of RBPs such as PTPB2. !


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: 2024 ( Subtotal = $0 )
2024	2022	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 N STATE COLLEGE BLVD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	000	4	8/28/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $106,500 )
2022	2022	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	000	4	3/25/2022	NON-COMPETING CONTINUATION	$95,850
2022	2022	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	001	4	6/20/2022	NON-COMPETING CONTINUATION	$10,650
														Subtotal = $106,500

Issue Date FY: 2021 ( Subtotal = $106,500 )
2021	2021	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	000	3	3/23/2021	NON-COMPETING CONTINUATION	$106,500
														Subtotal = $106,500

Issue Date FY: 2020 ( Subtotal = $106,500 )
2020	2020	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	000	2	3/26/2020	NON-COMPETING CONTINUATION	$106,500
														Subtotal = $106,500

Issue Date FY: 2019 ( Subtotal = $106,500 )
2019	2019	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	000	1	3/6/2019	NEW	$106,500
														Subtotal = $106,500

Grand Total All Awards = $426,000

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Role of Phosphorylation in RNA Binding Protein Function

Award Number: SC3GM132036

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: 04/01/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2024

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