The cutaneous microcirculation plays a central role in a range of skin diseases that are characterized by epidermal hyperproliferation or inflammation. Many of these diseases are typified by increased vascular permeability, which causes cutaneous edema and exacerbation of disease. In addition, altered vascular organization and/or neovascularization are associated with psoriasis, skin tumorigenesis, and with tissue remodeling during wound healing. Adhesive interactions between adjacent endothelial cells play a central role in both vascular permeability and in the reorganization and growth of endothelial cells during angiogenesis. VE-cadherin is a cell surface adhesion molecule specific to endothelial cells and plays a crucial role in endothelial growth control, vascular barrier function and in morphogenic events associated with angiogenesis. The extracellular domain of VE- cadherin mediates cell to cell contact, whereas the cytoplasmic tail of VE-cadherin binds to a series of proteins termed catenins, which couple VE-cadherin to actin and regulate VE-cadherin adhesion. Our work has shown that p120-catenin is a VE-cadherin binding partner that associates with the cadherin tail and prevents VE-cadherin endocytosis and degradation. Further, conditional gene ablation experiments showed that deletion of endothelial p120-catenin leads to vascular malformations and hemorrhage during development. Recently, we found that E3 ubiquitin ligases target VE-cadherin for endocytosis and degradation. Thus, cadherin endocytosis is highly regulated and appears to be important for vascular patterning and function. Here, we will explore the function of two different endocytic signals in the VE-cadherin tail that we have recently identified. We hypothesize that VE-cad endocytosis confers adhesive plasticity that is necessary for endothelial cell polarity and migration during normal vascular development, and that ubiquitin ligases cause aberrant VE-cad endocytosis and degradation.
Aim 1 studies will use a series of approaches in both cell culture and in mouse genetic models to determine how VE-cadherin endocytosis regulates endothelial cell polarity and migration, and how these processes contribute to normal vascular development.
Aim 2 studies will focus on a MARCH family E3 ubiquitin ligase expressed in Kaposi sarcoma endothelial tumors. Further, we will identify the endogenous MARCH family E3 ligases that are expressed in endothelial cells and which target VE-cadherin for degradation during development and skin disease. Completion of these studies will advance our understanding of cadherin based adhesion mechanisms and reveal possible therapeutic targets to regulate angiogenesis and inappropriate vascular regression.
These studies are designed to generate new insights into the basic cellular mechanisms that regulate cell-cell adhesion, and to expose new therapeutic targets for the treatment of skin diseases characterized by alterations in vascular function and inflammation.
| Su, Wenji; Kowalczyk, Andrew P (2017) The VE-cadherin cytoplasmic domain undergoes proteolytic processing during endocytosis. Mol Biol Cell 28:76-84 |
| Garrett, Joshua P; Lowery, Anthony M; Adam, Alejandro P et al. (2017) Regulation of endothelial barrier function by p120-catenin?VE-cadherin interaction. Mol Biol Cell 28:85-97 |
| Nanes, Benjamin A; Grimsley-Myers, Cynthia M; Cadwell, Chantel M et al. (2017) p120-catenin regulates VE-cadherin endocytosis and degradation induced by the Kaposi sarcoma-associated ubiquitin ligase K5. Mol Biol Cell 28:30-40 |
| Cadwell, Chantel M; Su, Wenji; Kowalczyk, Andrew P (2016) Cadherin tales: Regulation of cadherin function by endocytic membrane trafficking. Traffic 17:1262-1271 |
| Cadwell, Chantel M; Jenkins, Paul M; Bennett, Vann et al. (2016) Ankyrin-G Inhibits Endocytosis of Cadherin Dimers. J Biol Chem 291:691-704 |
| Stahley, Sara N; Kowalczyk, Andrew P (2015) Desmosomes in acquired disease. Cell Tissue Res 360:439-56 |
| Kowalczyk, Andrew P; Green, Kathleen J (2013) Structure, function, and regulation of desmosomes. Prog Mol Biol Transl Sci 116:95-118 |
| Oas, Rebecca G; Nanes, Benjamin A; Esimai, Chimdimnma C et al. (2013) p120-catenin and ?-catenin differentially regulate cadherin adhesive function. Mol Biol Cell 24:704-14 |
| Nanes, Benjamin A; Chiasson-MacKenzie, Christine; Lowery, Anthony M et al. (2012) p120-catenin binding masks an endocytic signal conserved in classical cadherins. J Cell Biol 199:365-80 |
| Saito, Masataka; Tucker, Dana K; Kohlhorst, Drew et al. (2012) Classical and desmosomal cadherins at a glance. J Cell Sci 125:2547-52 |
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