Tuesday, July 1, 2025 7/1/2025

Mechanisms and functions of Shoc2-transduced cellular signals

Award Number: R35GM136295
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: 05/01/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2025

Group Awards By:

View Award Description

Mechanisms and functions of Shoc2-transduced cellular signals - The overall vision of our NIGMS-supported program is to address the molecular mechanisms of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) signal transmission as guided by scaffold proteins. Essential for the normal functioning of the cell, the ERK1/2 ability to “rewire” signaling pathways is a major problem for clinical intervention. The rationale for the proposed studies is that a thorough understanding of the mechanism by which key regulators, such as scaffold protein Shoc2, modify ERK1/2 signaling is essential for understanding dysregulated mechanisms in ERK1/2-related diseases and for identifying new drug targets. Our studies have raised many exciting questions, and the most transformative research will be pursued in the next five-year period. Our efforts during the first cycle of NIGMS funding led to the discovery that the ubiquitin machinery regulates the signal transmission of ERK1/2 signals through the Shoc2 scaffolding module and controls assembly of the proteins in the complex. We identified key enzymes modulating the ability of Shoc2 to transmit ERK1/2 signals. We then discovered that organized spatial distribution of the Shoc2 complexes is critical for the proper transmission of ERK1/2 signals. Our work further revealed a distinct function of the signals transduced by the Shoc2 scaffold in ERK1/2 in mediating cell adhesion and motility. We also established that loss of Shoc2 in zebrafish has a systemic effect of on early development recapitulating congenital malformations observed in patients with Shoc2 mutations. For MIRA application, we propose to define the mechanisms by which endosomal sorting regulates the ubiquitin-driven remodeling of the Shoc2 complexes and signaling. The key steps that segregate Shoc2 into the distinct intracellular sorting pathways will be delineated. The molecular details of how Shoc2-activated ERK1/2 signals promote early developmental stages will be determined. We will use an innovative comprehensive approach encompassing genetic, state-of-the-art microscopy, as well as cell-based and biophysical methodologies. Of note, we will use zebrafish as a vertebrate model to investigate the in vivo effect of Shoc2 gene editing on the early stages of development since they offer distinct advantages for studies of development, including their transparency, as well as external and rapid development. The proposed research is expected to produce an ambitious and comprehensive mechanistic understanding of how Shoc2 is involved in determining the specificity of ERK1/2 signaling outcomes, and has the potential for high impact by laying the groundwork for future studies on developmental disorders and contributing to the advancement of novel therapeutic strategies and biomarkers.


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 = $0 )
2025	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Biomedical Research and Research Training	000	5	11/4/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $382,498 )
2024	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Biomedical Research and Research Training	001	5	8/6/2024	NON-COMPETING CONTINUATION	$38,251
2024	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Biomedical Research and Research Training	000	5	3/18/2024	NON-COMPETING CONTINUATION	$344,247
														Subtotal = $382,498

Issue Date FY: 2023 ( Subtotal = $617,025 )
2023	2023	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Biomedical Research and Research Training	001	4	8/25/2023	SUPPLEMENT FOR EXPANSION	$234,527
2023	2023	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Biomedical Research and Research Training	000	4	4/24/2023	NON-COMPETING CONTINUATION	$382,498
														Subtotal = $617,025

Issue Date FY: 2022 ( Subtotal = $382,498 )
2022	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Biomedical Research and Research Training	000	3	4/25/2022	NON-COMPETING CONTINUATION	$382,498
														Subtotal = $382,498

Issue Date FY: 2021 ( Subtotal = $407,623 )
2021	2021	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Biomedical Research and Research Training	001	2	8/2/2021	SUPPLEMENT FOR EXPANSION	$25,125
2021	2021	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Biomedical Research and Research Training	000	2	4/20/2021	NON-COMPETING CONTINUATION	$382,498
														Subtotal = $407,623

Issue Date FY: 2020 ( Subtotal = $357,319 )
2020	2020	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Biomedical Research and Research Training	000	1	4/9/2020	NEW	$357,319
														Subtotal = $357,319

Grand Total All Awards = $2,146,963

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Mechanisms and functions of Shoc2-transduced cellular signals

Award Number: R35GM136295

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: 05/01/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2025

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer