A novel role for p115RhoGEF in regulation of epithelial plasticity.

Epithelial plasticity plays a critical role during physiological processes, such as wound healing and tissue regeneration, and dysregulation of epithelial plasticity can lead to pathological conditions, such as cancer. Cell-cell junctions are a critical feature of epithelial cells and loss of junctions is associated with acquisition of mesenchymal features, such as enhanced protrusion and migration. Although Rho has been implicated in regulation of junctions in epithelial cells, the role of Rho signaling in the regulation of epithelial plasticity has not been understood.

PDZ-RhoGEF is essential for CXCR4-driven breast tumor cell motility through spatial regulation of RhoA.

The CXCL12-CXCR4 chemokine signaling pathway is a well-established driver of cancer progression. One key process promoted by CXCR4 stimulation is tumor cell motility; however, the specific signaling pathways leading to migration remain poorly understood. Previously, we have shown that CXCL12 stimulation of migration depends on temporal regulation of RhoA.

Nuanced junctional RhoA activity.

RhoA signalling controls many diverse cellular processes, and thus discovering the mechanisms that determine its specific outcomes is a tantalizing challenge. A previously uncharacterized regulatory module operates selectively at the zonula adherens of epithelial cell junctions, in which positive and negative RhoA regulators are coordinated to fine-tune RhoA activity.

Regulation of ROCKII membrane localization through its C-terminus.

RhoA activated kinases (ROCKs) are potent effectors of RhoA signaling for regulation of the cytoskeleton. ROCKs have been shown to be localized to several different subcellular locations, suggesting that its localization is context specific and regulated. However, the signaling mechanisms that control ROCK localization have not been clearly described.

Regulation of ROCKII by localization to membrane compartments and binding to DynaminI.

ROCKII kinase activity is known to be regulated by Rho GTPase binding; however, the context-specific regulation of ROCKII is not clearly understood. We pursued the C-terminal PH domain as a candidate domain for regulating ROCKII function. A proteomics-based screen identified potential ROCKII signaling partners, a large number of which were associated with membrane dynamics.