Signals Control Endothelial Barrier Integrity

Endothelial cells line blood vessels and form a semi-permeable barrier. Endothelial dysfunction contributes to many pathological conditions including cardiovascular disease, cancer and sepsis progression. During vascular inflammation and injury breakdown of the endothelial barrier occurs. We are examining how activation of GPCRs, specifically PARs, by distinct proteases differentially regulates endothelial barrier breakdown (pro-inflammatory signaling) versus cytoprotection (anti-inflammatory signaling) through selective activation of specific signaling pathways. The molecular mechanisms by which ubiquitin and subcellular compartmentalization mediate endothelial PAR signaling is also being actively investigated.

Signaling and Breast Cancer Progression

GPCRs are the largest class of signaling receptors expressed in mammalian cells and regulate many aspects of cancer pathogenesis. The protease-activated GPCR, PAR1 has been implicated n progression of multiple cancers including breast cancer. Signaling by protease-activated GPCRs is tightly regulated through rapid desensitization and endocytic trafficking. We discovered that aberrant PAR1 trafficking results in dysregulated signaling in invasive breast cancer and consequently promotes tumor progression. We are examining how the endocytic machinery and the tumor suppressor ARRDC3 contribute to the dysregulation of PAR1 trafficking and signaling to the Hippo pathway and the impact on breast carcinoma growth, invasion and metastasis.