This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Endothelial cell migration is a key step towards tumor angiogenesis that is essential for tumor growth and metastasis. The focus of this research is to understand how caveolin, an endogenous inhibitor of signaling molecules, functions in spatial organization of the activity of signal molecules that direct cell movement and in endothelial cell polarity and migration. Caveolin, a caveolar membrane coating protein, is highly expressed in quiescent endothelial cells. Its expression is dramatically suppressed in glioma endothelial cells and in human cancers. Our primary interest is the role of caveolin asymmetry in endothelial cell migration. We have shown that caveolin-1 was polarized toward the rear of a migrating cell. Loss of caveolin polarity impeded endothelial cell directional movement. Thus, during cell migration, caveolin-1 moves to cell rear as a mechanism to sequester it away from signaling proteins that direct lamellipod protrusion. This proposal seeks to understand how caveolin-1 regulates endothelial cell migration by testing the following hypotheses: (a) a specific sequence or domain directs caveolin-1 relocation to the rear of a migrating cell; and (b) caveolin-1 polarity is critical for spatial organization of signaling events that mediate lamellipod protrusion.
The specific aims of this project are: (1) To discern the sequence motifs responsible for the control of caveolin-1 polarity in a moving cell. A series of domain deletion and sequence mutations of caveolin-1 as GFP-fusion proteins will be generated to determine a specific mutant that fails to move to the rear of a migrating cell; and (2) To determine whether caveolin-1 polarity is critical for spatial organization of FAK/PI 3-K/Rac-1 activity that directs lamellipod protrusion. Two models of caveolin-1 depolarization, i.e. caveolin-1 null cells or caveolin-1 null cells engineered to express caveolin-1 mutant that fails to polarize, will be used to determine the role of Cav-1 polarity in spatial organization of signaling events that direct lamellipod protrusion. Completion of the proposed studies will reveal a critical role of caveolin in orienting endothelial cell directional movement that is relevant to tumor angiogenesis.
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