Many cell types require attachment to the extracellular matrix in order to proliferate in response to soluble growth factors, and indeed, to survive. Hallmark characteristics of cancer cells are their reduced or altered dependence upon adhesion for proliferation and survival, contributing to inappropriate growth in the animal. Furthermore, defective integration of signals from adhesion and soluble factors may contribute to inappropriate motility during metastasis, or to defects in immune cell function. ERK has been implicated in each of these disease states, and adhesion signaling is found to play essential roles in both proliferative and migratory responses in tissue culture. Consequently, the poorly understood mechanisms by which adhesion and growth factor signals are integrated to modify the duration and localization of ERK signaling during these key normal and pathologic processes are of considerable intellectual and clinical interest. I propose to investigate these mechanisms in two Specific Aims: I. Integration Of Adhesion And Growth Factor Signals Through Molecular Scaffolding. MEK can serve as an anchorage-sensor for growth factor signaling to ERK, although the mechanisms by which it confers anchorage dependence are unknown. We will focus on MEK1 phosphorylation and assembly of MEKl-specific signaling complexes as points of integration for adhesion and growth factor signals. The properties of MP1, a MEK1-specific binding partner, suggest it plays a key role in the assembly of such signaling complexes. We will also identify novel, phosphorylation-dependent binding partners predicted to integrate adhesion and growth factor signaling by scaffolding MEK1 with relevant kinases and small GTPases. The contribution of MEK1 phosphorylation and binding partners to anchorage-independent ERK signaling will be assessed. II. Signal Integration At MEK1 During Chemotaxis. Our data reveal MEKl-specific mechanisms for localized ERK activation in lamellipodia. Since MEK1-, but not MEK2-nulI, fibroblasts show migration defects, we will use reconstitution experiments to quantitate the contribution of MEK1 binding partners and phosphorylation sites to both the morphological and gradient-sensing processes necessary for chemotaxis. To complement these studies, we will investigate the subcellular localization of the phospho-forms of MEK1 and relevant known and newly identified binding partners in chemotaxing cells. These studies have the potential to reveal a universal mechanism by which MEK1 senses both adhesion and growth factor signals to regulate directional cell motility.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM068111-03
Application #
6890334
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Anderson, Richard A
Project Start
2003-06-01
Project End
2008-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
3
Fiscal Year
2005
Total Cost
$249,920
Indirect Cost
Name
Louisiana State University Hsc New Orleans
Department
Pharmacology
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
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