Copines are highly conserved calcium-dependent membrane-binding proteins found in numerous diverse eukaryotic organisms. The wide array of organisms ranging from single-celled organisms to humans in which copines are found suggest that copines carry out fundamental functions important in most eukaryotic cells. A growing body of evidence indicates that copines act as regulatory proteins in signaling pathways. The model organism Dictyostelium discoideum has six copine genes (cpnA-cpnF) and provides an ideal system for studying copine function. Dictyostelium can live independently as single-celled amoebae, but when placed in starvation conditions, single amoeba signal each other to first aggregate and then differentiate into cells that form a multicellular fruiting body. This simple developmental program in Dictyostelium is widely used to study not only development, but also several basic cell processes including chemotaxis-mediated cell motility, signal transduction, programmed cell death, and cell differentiation. Previous studies showed that one of the copine proteins in Dictyostelium, CpnA, is required for normal development. The overall goal of the previous grant award was to correlate our findings on cpnA- cells during developmental processes (aim 1) and the identification of the target proteins of CpnA (aim 2) to generate more specific hypotheses about the function of CpnA. Significant progress was made on both of these specific aims and data collected during the previous grant award period has led to two new hypotheses about the function of CpnA. These two hypotheses form the two specific aims of this renewal proposal: 1) Determine if CpnA is a negative regulator of the cAMP phosphodiesterase, RegA and 2) Determine if CpnA is a negative regulator of actin filament polymerization. This grant proposal describes experiments using biochemical, genetics, and microscopy approaches to test these hypotheses. The results of these experiments will make a significant impact on this field by being the first to define a mechanistic role for a copine protein. Human copines have been implicated to play a role in cancer by regulating signaling pathways involving the ErB2 receptor and in immune responses by regulating signaling pathways involving the TNF (tumor necrosis factor) receptor. Increasing our scientific knowledge of how copines function could lead to a better understanding of cancer and immune cell-related diseases.

Public Health Relevance

The proposal outlines experiments to investigate the functions of a novel family of proteins called copines. Copines are hypothesized to have roles in cell signaling pathways, but their exact functions are unknown. The human genome has eight copine genes and copines have been implicated in cancer and immune responses. Increasing our scientific knowledge of how copines function could potentially lead to a better understanding of cancer and immune-cell related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
2R15GM078089-02
Application #
8434437
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Chin, Jean
Project Start
2008-07-01
Project End
2015-12-31
Budget Start
2013-01-15
Budget End
2015-12-31
Support Year
2
Fiscal Year
2013
Total Cost
$313,953
Indirect Cost
$86,926
Name
Central Michigan University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
624134037
City
Mount Pleasant
State
MI
Country
United States
Zip Code
48859
Flegel, Kerry A; Pineda, Jaimie M; Smith, Tasha S et al. (2011) Copine A is expressed in prestalk cells and regulates slug phototaxis and thermotaxis in developing Dictyostelium. Dev Growth Differ 53:948-59
Smith, Tasha S; Pineda, Jaimie M; Donaghy, Alex C et al. (2010) Copine A plays a role in the differentiation of stalk cells and the initiation of culmination in Dictyostelium development. BMC Dev Biol 10:59