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Activation of protein kinases by proline hydroxylation

Award Number: R01CA280560
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/05/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Activation of protein kinases by proline hydroxylation - Project summary Eukaryotic protein kinases regulate important cellular processes through their ability to phosphorylate themselves and substrate proteins. One of the phosphorylation events common to most protein kinases is the phosphorylation that occurs at the activation loop. This phosphorylation event often occur via auto- phosphorylation although how an inactive kinase achieves the phospho-transfer reaction on its own activation loop site is still unclear [2]. We recently reported that activation of dual specificity tyrosine-phosphorylation- regulated kinases 1A and 1B (DYRK1A and DYRK1B) requires prolyl-hydroxylation by the oxygen sensing prolyl hydroxylase PHD1. DYRK1 activation by prolyl-hydroxylation instigates a sequence of events whereby phosphorylation of ID2 by DYRK1 releases ID2 mediated constraints on VHL ubiquitin ligase tumor suppressor complex, thus regulating the degradation of HIF proteins in brain tumors and cancer stem cells. Our most recent work identified prolyl hydroxylation by PHD1 as the general mechanism required in trans to prime protein kinases of the CMGC family for autophosphorylation and activation. Beside DYRK1, CMGC kinases includes Cyclin dependent kinases (C), Mitogen activated protein kinases (M), Glycogen synthase kinases (G) and CDC-like kinases (C). In this proposal we will follow the long-standing interest of the lab on the molecular pathways that favor neural cell self-renewal during brain development and are aberrantly recruited during gliomagenesis and investigate the mode of regulation of glycogen synthase kinase 3 (GSK3), a central hub in the control of brain functions and oncogenesis. GSK3 shares with other members of the CMGC kinase family the highly conserved CMGC insert domain. We found that this domain harbors a L/xGxP motif and the highly conserved proline residue, Pro-276, which is targeted by hydroxylation by the proline hydroxylase enzyme PHD1 and is necessary for kinase activation. These observations led us to propose a combination of mechanistic and genetic studies to define the dynamics of GSK3a/b kinase maturation induced by PHD1 and the interaction with other signaling mechanisms that regulate GSK3 kinase activity. The significance of proline hydroxylation for gliomagenesis will be investigated in knock-in mouse models of Pro to Ala mutation of GSK3a/b (Pro-339 and Pro-276, respectively). Mouse tumors will be analyzed using proteomics and phosphoproteomics to reconstruct the activity of wild type and mutant GSK3 kinases. Given the uncertain role of GSK3 kinases in cancer and glioblastoma (promoter or suppressor), findings will lead to a better understanding of the potential benefit/harm of GSK3 inhibitors that are currently proposed for the treatment of glioblastoma.


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 = $446,036 )
2025	2025	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Cancer Biology Research	000	2	12/16/2024	NON-COMPETING CONTINUATION	$401,433
2025	2025	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Cancer Biology Research	001	2	6/3/2025	NON-COMPETING CONTINUATION	$44,603
														Subtotal = $446,036

Issue Date FY: 2024 ( Subtotal = $446,036 )
2024	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Cancer Biology Research	000	1	1/5/2024	NEW	$446,036
														Subtotal = $446,036

Grand Total All Awards = $892,072

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Activation of protein kinases by proline hydroxylation

Award Number: R01CA280560

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/05/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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