Understanding cell motility, including its mechanisms and consequences, is central to understanding the body's defenses against infection, the healing processes following tissue injury, and normal development. Cell migration also contributes to pathologic conditions such as bone resorption that occurs during chronic inflammatory diseases such as rheumatoid arthritis, and cancer invasion and metastasis. We have found that a family of LIM domain-containing proteins regulate cell adhesion and cell migration in three different, yet over-lapping, systems. In migrating fibroblasts they regulate lamellipodia production, adhesion formation and turnover, and thus migration. In macrophages they regulate the phagocytosis, and thus immune clearance, of an enteric pathogenic bacterium. In bone osteoclasts they regulate adhesion, migration and bone resorption. All three processes require signal-regulated reorganization of the actin cytoskeleton, in part, through the formation and activation of a FAK-Src-p130Cas protein complex at the respective adhesive structures and plus the localized synthesis of phosphoinositol lipids. Based on our preliminary data we hypothesize that these LIM proteins regulate cell adhesion and function in each cell type by affecting the assembly and activation of the FAK-Src-p130Cas complex and, or phosphoinositol lipid synthesis. We propose to biochemically determine and contrast how these LIM proteins regulate cell adhesion, migration and cell function in all three systems using primary cells derived from mice deficient in family members of this LIM protein family and in vivo. There are 3 specific aims:
Specific Aim 1 : To determine how Ajuba LIM proteins regulate fibroblast adhesion and migration.
Specific Aim 2 : To determine how Ajuba LIM proteins regulate macrophage phagocytosis of bacteria.
Specific Aim 3 : To determine how Ajuba LIM proteins regulate bone osteoclasts function. ? ? ?
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