Cytoskeletal rearrangement (i.e. assembly and disassembly of the cytoskeleton) is necessary for many different cellular processes such as cell motility, cytokinesis, and membrane traffic. These processes are governed by signal transduction pathways involving a cascade of events in which Rho G proteins and Dbl family proteins play a key role. Aberrations in the regulation of these proteins leads to oncogenic cellular transformation. All Dbl proteins are characterized by the presence of a conserved DH domain followed by a PH domain. The PH domain is a membrane-targeting domain which acts to localize proteins to the membrane through PH domain interactions with phosphoinositides, while the DH domain is responsible for activation of the Rho G protein which propagates the signal downstream. Several studies suggest that the PH domains Dbl proteins regulate the DH domain. Our goal is to understand the role of the PH domain in control of the DH domain in Dbl family proteins. This understanding is essential for the appreciation of cell growth regulation and migration and for potential approaches to pharmacological intervention.
The specific aim are: 1. We will test the hypothesis that weak Ptdlns binding by the PH domain in Dbl proteins is important for the normal GEF activity of the full-length protein in-vivo. 2. We will test the hypothesis that Dbl proteins utilize a mechanism of regulated avidity, involving the PH domain, for membrane targeting and exchange activity on Rho family G proteins. 3. We will test the hypothesis that Dbl proteins contain other domains such as oligomerization domains, or membrane targeting, domains that function to increase membrane binding avidity.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31GM065066-04
Application #
6791448
Study Section
Special Emphasis Panel (ZRG1-CDF-6 (20))
Program Officer
Toliver, Adolphus
Project Start
2002-09-01
Project End
2005-03-15
Budget Start
2004-09-01
Budget End
2005-03-15
Support Year
4
Fiscal Year
2004
Total Cost
$19,566
Indirect Cost
Name
University of Pennsylvania
Department
Biochemistry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104