FAT cadherins and vascular remodeling

FAT cadherins and vascular remodeling Vascular remodeling is a critical process in the pathogenesis of major vascular diseases such as atherosclerosis, restenosis, saphenous vein graft occlusion, and transplant-associated arteriosclerosis. Factors that control the activities of vascular smooth muscle cells (SMCs) during vascular remodeling remain incompletely understood. Fat cadherins belong to an ancient family of large, single pass type I transmembrane proteins found throughout Metazoans; conserved functions of these proteins affect cell growth and polarity and span from Drosophila to mammals. The FAT1 cadherin is expressed by SMCs in multiple animal models of vascular disease and in injured human arteries. We have found that inactivation of the Fat1 locus in SMCs permits dramatic increases in proliferation and neointimal formation in a mouse model of vascular injury. Interestingly, the FAT1 molecule undergoes complex processing: while cleavage and translocation of the FAT1 intracellular domain (ICD) to the cell nucleus was reported several years ago, we found an accumulation of FAT1 fragments within mitochondria, wherein these FAT1mito species interact selectively with inner membrane proteins and exert critical regulatory control over oxidative phosphorylation, limiting the activities of respiratory Complexes I and II and inhibiting cell growth. FAT1 also has substantial effects on SMC gene expression, promoting expression of SMC marker genes both in vitro and in vivo; interestingly, the FAT1ICD is also found in the cell nucleus, raising the possibility of more direct involvement in gene regulation. In this project, we will assess how FAT1 signals from different locations within the cell, and assess whether these activities are complementary, oppositional, or overlapping to control SMC phenotype. We will investigate intra- and extracellular sequences in FAT1 and interactions with structurally-related proteins FAT4 and DCHS1 that may control how FAT1 is processed and thereby directed to distinct compartments. To assess relevance to key disease processes in vivo, we will assess how these signaling activities affect vascular remodeling and atherosclerosis in mouse models.