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Understanding Signaling by Non-Canonical Receptor Tyrosine Kinases

Award Number: R35GM122485
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: 05/01/2017
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Understanding Signaling by Non-Canonical Receptor Tyrosine Kinases - The research proposed in this MIRA renewal application seeks to understand mechanisms of transmembrane signaling by members of the receptor tyrosine kinase (RTK) superfamily – and other receptor-like kinases – that do not fit the ‘rules’ that explain most RTKs. Non-canonical receptors in this group play important roles in human disease – from neurodevelopmental disorders, to bone diseases, cancers, and congenital malformations. The traditional model for RTK signaling involves ligand-induced receptor dimerization, which promotes tyrosine autophosphorylation of the receptor and recruitment of downstream signaling molecules. As we understand more about the 58 human RTKs, it has become clear that this mechanism only applies to about half of them. For example, 10% of human RTKs are linked to WNT signaling, and must function differently because their intracellular regions often have only catalytically inactive ‘pseudokinase’ domains. Still other RTKs (such as ALK) have unique extracellular regions for which ligand binding and receptor regulation are poorly understood. We have made significant progress in understanding extracellular and intracellular structures of WNT-regulated pseudokinase RTKs. Their extracellular WNT-binding modules differ significantly from their counterparts in proteins involved in ‘canonical’ WNT signaling, in ways that suggest well-defined hypotheses for how these RTKs might participate as co-receptors with Frizzled receptors in b-catenin independent WNT signaling. The intracellular pseudokinase domains of the RTKs structurally resemble the insulin receptor kinase in its ‘inactive’ conformation, and analysis of their structural dynamics suggests that they can undergo the same ‘inactive-like’ to ‘active-like’ conformational transitions seen for normal tyrosine kinase domains. Indeed, we have found that these transitions can be promoted by small molecule kinase inhibitor-like molecules, despite the fact that the isolated pseudokinase domains do not bind ATP. In the next 5-10 years of this project, we propose to test hypotheses for WNT-induced assembly of receptor complexes that incorporate pseudokinase RTKs, elucidate their specific WNT dependence and reliance on WNT acylation, gain high resolution structural views through crystallography and EM, and analyze their signaling properties. We will test hypotheses for how the pseudokinase domains contribute to signaling – either by acquiring kinase activity or by functioning as allosterically switchable interaction platforms, with precedents in other pseudokinases and in catalytically active kinases such as Aurora A. In parallel with these efforts, we will investigate new opportunities for therapeutic targeting of pseudokinase RTKs such as PTK7, ROR1, ROR2, and RYK, which have all been implicated in numerous diseases. Together, these studies will provide important new insight into signaling by receptors that do not fit normal paradigms for RTKs or WNT receptors. The new lessons should also be applicable to other classes of receptor-like kinases implicated in disease, opening new avenues for potential therapeutic inhibition.


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 = $770,500 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	10	4/10/2026	NON-COMPETING CONTINUATION	$770,500
														Subtotal = $770,500

Issue Date FY: 2025 ( Subtotal = $770,500 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	001	9	4/17/2025	NON-COMPETING CONTINUATION	$770,500
2025	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	8	11/8/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $770,500

Issue Date FY: 2024 ( Subtotal = $770,500 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	001	8	8/5/2024	NON-COMPETING CONTINUATION	$77,050
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	8	3/27/2024	NON-COMPETING CONTINUATION	$693,450
														Subtotal = $770,500

Issue Date FY: 2023 ( Subtotal = $770,500 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	002	7	4/7/2023	NON-COMPETING CONTINUATION	$770,500
2023	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	001	6	11/22/2022	COMPETING CONTINUATION	$7,763
2023	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	5	11/22/2022	NON-COMPETING CONTINUATION	-$7,763
														Subtotal = $770,500

Issue Date FY: 2022 ( Subtotal = $770,500 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	6	3/29/2022	COMPETING CONTINUATION	$770,500
														Subtotal = $770,500

Issue Date FY: 2021 ( Subtotal = $803,411 )
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	5	4/13/2021	NON-COMPETING CONTINUATION	$803,411
														Subtotal = $803,411

Issue Date FY: 2020 ( Subtotal = $803,411 )
2020	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	4	4/10/2020	NON-COMPETING CONTINUATION	$803,411
														Subtotal = $803,411

Issue Date FY: 2019 ( Subtotal = $793,758 )
2019	2019	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	3	4/12/2019	NON-COMPETING CONTINUATION	$793,758
														Subtotal = $793,758

Issue Date FY: 2018 ( Subtotal = $879,000 )
2018	2018	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	001	2	9/14/2018	SUPPLEMENT FOR EXPANSION	$75,000
2018	2018	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	2	4/20/2018	NON-COMPETING CONTINUATION	$804,000
														Subtotal = $879,000

Issue Date FY: 2017 ( Subtotal = $804,000 )
2017	2017	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	1	4/17/2017	NEW	$804,000
														Subtotal = $804,000

Grand Total All Awards = $7,936,080

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Understanding Signaling by Non-Canonical Receptor Tyrosine Kinases

Award Number: R35GM122485

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: 05/01/2017

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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