A Novel Role for p115RhoGEF in Regulation of Epithelial Plasticity

Abstract

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. We show that members of the RGS RhoGEFs family play a critical role in regulation of epithelial cell-cell junctions in breast epithelial cells. We identify a novel role for p115RhoGEF in regulation of epithelial plasticity. Loss of p115RhoGEF leads to decreased junctional E-cadherin and enhanced protrusiveness and migration. Conversely, overexpression of p115RhoGEF enhanced junctional E-cadherin and inhibited cell protrusion and migration. siRNA screen of 23 Rho effectors showed that members of the Diaphanous-Related Formin (DRF) family are required for p115RhoGEF-mediated changes in epithelial plasticity. Thus, our data indicates a novel role for p115RhoGEF in regulation of epithelial plasticity, which is dependent on Rho-DRF signaling module.

Arhgef1 negatively regulates neurite outgrowth through activation of RhoA signaling pathways

“…These Arhgef1 mutants were first tested for their GEF activities. As shown previously in immune system and cancer cells that Arhgef1 is a selective GEF for RhoA activation , we observed strong activation of RhoA by Arhgef1 expression in neuronal cells (Fig. B).…”

“…Loss of Arhgef1 in the immune system of mice causes disrupted homeostatic lung immunity and pulmonary pathology . Other reported Arhgef1 functions include regulation of epithelial cell plasticity and vasculature . However, whether Arhgef1 has a role in the nervous system has not been explored.…”

MAP2K1 is a potential therapeutic target in erlotinib resistant head and neck squamous cell carcinoma

“…We observed focal amplification and 2 fold protein overexpression of YAP1 which is a reported oncogenic target of 11q22 amplification in multiple cancer subtypes including HNSCC 47,48 and shown to promote resistance to erlotinib in NSCLC 49 . In addition, we observed copy number gain and a corresponding 3.9 fold overexpression of ARHGEF1, which is known to regulate epithelial cell plasticity and contribute to EMT in breast cancer cell lines 50 . We observed protein downregulation of NF1 and copy number loss in SCC-R cells.…”

RhoGTPases, actomyosin signaling and regulation of the Epithelial Apical Junctional Complex

“…Additionally, decreased activation of Cdc42 and Rac1 correlates with increased invasive potential of several epithelial cell lines derived from metastatic colorectal adenocarcinoma [114]. In breast epithelial cells p115RhoGEF loss leads to decreased junctional E-cadherin and enhanced migration [115], whereas ROCK inhibition disrupts the AJC and promotes cell proliferation and migration [116]. …”