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Integration of Phosphatidylinositol and Diphosphoinositol Signals at the Exocyst

Award Number: R15GM106322
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: 09/15/2015
PERIOD OF PERFORMANCE END DATE: 08/31/2021

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Integration of Phosphatidylinositol and Diphosphoinositol Signals at the Exocyst - DESCRIPTION (provided by applicant): Our objectives are to define the role of the inositol kinase PPIP5K at the exocyst and determine if its activation impacts exocyst interaction with the GTPase RalA. This investigation is significant because RalA activation and its association with the exocyst complex are essential steps for Ras-driven cancer development and anchorage-independent growth. Diphosphoinositols are known to compete with inositol membrane lipids for binding to PH domains, and PIP2 inhibits RalA association with the exocyst. We propose to test the hypothesis that PPIP5K is activated by interaction with exocyst subunits and produces diphosphoinositols that promotes RalA interaction with the exocyst. This model will form the basis for a new strategy to target oncogenic Ras signaling through PPIP5K inhibition thereby preventing RalA action. This study builds on our existing work that identified PPIP5K as an exocyst-associated protein that desensitizes cells to apoptosis-inducing agents. We will accomplish these objectives through three overlapping aims: 1. Map interactions between PPIP5K and the exocyst complex. We have identified PPIP5K as an exocyst-associated enzyme and in this aim we will identify the direct interactions between PPIP5K and the exocyst complex. This will contribute to our understanding of the exocyst assembly by linking PPIP5K to one of the sub-complexes that interact during exocyst assembly. This would place the kinase activity on either the vesicular membrane or plasma membrane, which will be a key site for defining the role of the diphosphoinositols produced. 2. Identify diphosphoinositol-binding exocyst subunits and its impact on RalA binding. Diphosphoinositols are produced at the exocyst and we will test if they impact interaction of RalA with this complex. In this aim, we will identify diphosphoinositol binding exocyst subunits, determine if these interactions prevent exocyst association with PIP2, and determine if this relieves inhibition of RalA binding by PIP2. 3. Define activation mechanism and activating trigger for PPIP5K. Diphosphoinositols are short-lived signaling molecules, so they are synthesized at their sites of action. PPIP5K kinase activity is inhibited by another domain of PPIP5K, but which domain performs this action and how the inhibition is relieved remains unknown. In this aim, we will identify the mechanism for its inhibition and determine how it is activated at the exocyst complex.


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: 2022 ( Subtotal = -$32,421 )
2022	2015	CATHOLIC UNIVERSITY OF AMERICA (THE)	620 MICHIGAN AVE NE	WASHINGTON	DC	20064	DISTRICT OF COLUMBIA	USA	Biomedical Research and Research Training	000	1	10/1/2021	NEW	-$32,421
														Subtotal = -$32,421

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2015	CATHOLIC UNIVERSITY OF AMERICA (THE)	620 MICHIGAN AVE NE	WASHINGTON	DC	20064	DISTRICT OF COLUMBIA	USA	Biomedical Research and Research Training	000	1	11/3/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2015	CATHOLIC UNIVERSITY OF AMERICA (THE)	620 MICHIGAN AVE NE	WASHINGTON	DC	20064	DISTRICT OF COLUMBIA	USA	Biomedical Research and Research Training	000	1	12/4/2019	NEW	$0
2020	2015	CATHOLIC UNIVERSITY OF AMERICA (THE)	620 MICHIGAN AVE NE	WASHINGTON	DC	20064	DISTRICT OF COLUMBIA	USA	Biomedical Research and Research Training	001	1	5/21/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2015	CATHOLIC UNIVERSITY OF AMERICA (THE)	620 MICHIGAN AVE NE	WASHINGTON	DC	20064	DISTRICT OF COLUMBIA	USA	Biomedical Research and Research Training	000	1	9/7/2018	NEW	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $238,833 )
2015	2015	CATHOLIC UNIVERSITY OF AMERICA	620 MICHIGAN AVE. N. E.	WASHINGTON	DC	20064	DISTRICT OF COLUMBIA	USA	Biomedical Research and Research Training	000	1	9/14/2015	NEW	$238,833
														Subtotal = $238,833

Grand Total All Awards = $206,412

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Integration of Phosphatidylinositol and Diphosphoinositol Signals at the Exocyst

Award Number: R15GM106322

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: 09/15/2015

PERIOD OF PERFORMANCE END DATE: 08/31/2021

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