The long-term goal of the proposed research is to understand how a family of G protein-coupled receptors (GPCRs), called adhesion GPCRs, transduces signals. Adhesion GPCRs have been recognized in recent years as critical regulators of diverse biological processes, but the mechanisms of their regulation remain unclear. A unique feature of adhesion GPCRs is that they are typically cleaved into two fragments. How these fragments contribute to their functions is not known. Substantial preliminary data have showed that the two cleaved fragments (GPRN and GPRC) of GPR56, a member of adhesion GPCRs, interact to regulate downstream signaling events, including the secretion of the vascular endothelial growth factor (VEGF) and the activation of protein kinase C? (PKC?) in melanoma cells. The goal of the proposed research is to use this system to further dissect the activation mechanisms of GPR56 and its signaling components.
Three specific aims are proposed: 1) Investigate whether GPRN regulates activities of GPRC. ELISA, co-immunoprecipitation, cell surface labeling, and mutagenesis analyses will be performed. 2) Examine whether GPRC regulates PKC? activity through G proteins. Minigene construct expression, small GTPase activity assay, reporter assays, and PKC membrane translocation analyses will be performed. 3) Investigate the desensitization mechanisms of GPRC. Mutagenesis analyses, radiolabeling assay, and expression analyses of shRNAs and mutant arrestins will be performed. Taken together;the outcome of the research will help to establish a paradigm on the signal transduction of adhesion GPCRs, a group of receptors that play essential roles in human development and diseases. Thus the proposed research is highly relevant to the mission of the National Institute of General Medical Sciences of NIH.

Public Health Relevance

The proposed research aims to build a frame-work for studying the functions of a group of poorly characterized but highly disease-related receptors. It is therefore highly relevant to public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM098591-01A1
Application #
8291805
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Dunsmore, Sarah
Project Start
2012-06-01
Project End
2017-03-31
Budget Start
2012-06-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$293,550
Indirect Cost
$103,550
Name
University of Rochester
Department
Genetics
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Yang, Liquan; Friedland, Scott; Corson, Nancy et al. (2014) GPR56 inhibits melanoma growth by internalizing and degrading its ligand TG2. Cancer Res 74:1022-31