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Regulation of tumorigenic G protein signaling by novel post-translational mechanisms

Award Number: R15CA309667
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Regulation of tumorigenic G protein signaling by novel post-translational mechanisms - Project Summary. For proteins implicated in human diseases such as cancer, therapeutic advances arise not only from discovering ways to manipulate their function directly, but also through indirect approaches such as investigating their regulation by other cellular molecules. Heterotrimeric G proteins of the G12/13 subfamily provide a good example; the GTP-binding a subunits - Ga12 and Ga13 - are substrates for several chemical modifications after their translation. Two such mechanisms, covalent attachment of a specific fatty acid (S- palmitoylation) and a phosphate group (phosphorylation), were reported soon after discovery of these G proteins; however, follow-up studies of these modifications have been sparse. The specific enzymes that covalently modify the G12/13 a subunits have not been identified. Because Ga12 and Ga13 harbor potent ability to drive tumorigenic signaling and metastatic invasiveness in cells, and recently were implicated as conferring stem cell-like properties upon tumor initiating cells, methods of disrupting or manipulating their signaling could lead to useful therapeutics. My laboratory's undergraduates used mutagenic strategies to either nullify or mimic phosphorylation of Ga12 and Ga13 at selected amino acids, and recently obtained experimental results for Ga12 that point to a rarely observed cross-regulatory mechanism between its phosphorylation and S-palmitoylation. This putative mechanism, in which down-regulated S-palmitoylation of Ga12 disrupts its ability to drive tumorigenic signaling, has not been reported for any G protein. The first phase of this proposal describes a plan to “dissect” this cellular mechanism by i.) identifying enzymes that catalyze S-palmitoylation and phosphorylation of Ga12, ii.) revealing the contextual amino acids in Ga12 that allow its specific targeting, and iii.) developing assays to detect the S-palmitoylation and/or phosphorylation of recombinant Ga12 mutants expressed in cultured human cells. The second phase of this proposal also arose from a discovery by UNC Asheville undergraduates: a new mechanism in which activation of protein kinase A (PKA) drives a steep increase in the already potent tumorigenic signaling by both Ga12 and Ga13. A combination of mutagenesis, signaling assays, and molecular probes will be employed to investigate the components of this regulatory mechanism. Interestingly, the responses of Ga12 and Ga13 to PKA activation show several differences that will be investigated. An overarching goal of the proposed studies is to discover distinct features of tumorigenic signaling by the G12/13 subfamily, not only in comparison to other G protein a subunits but between Ga12 and Ga13 themselves. Such information should provide value toward developing therapeutics against cancers in which aberrant signaling by a specific G protein plays a role.


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 = $428,396 )
2026	2026	THE UNIVERSITY OF NORTH CAROLINA AT ASHEVILLE	1 UNIVERSITY HEIGHTS	ASHEVILLE	NC	28804	BUNCOMBE	USA	Cancer Biology Research	000	1	3/27/2026	NEW	$428,396
														Subtotal = $428,396

Grand Total All Awards = $428,396

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Regulation of tumorigenic G protein signaling by novel post-translational mechanisms

Award Number: R15CA309667

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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