Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:O15085 (PDZ-RhoGEF)
 91 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study we have examined CD44 (a hyaluronan (HA) receptor) interaction with a RhoA-specific guanine nucleotide exchange factor (p115RhoGEF) in human metastatic breast tumor cells (MDA-MB-231 cell line). Immunoprecipitation and immunoblot analyses indicate that both CD44 and p115RhoGEF are expressed in MDA-MB-231 cells and that these two proteins are physically associated as a complex in vivo. The binding of HA to MDA-MB-231 cells stimulates p115RhoGEF-mediated RhoA signaling and Rho kinase (ROK) activity, which, in turn, increases serine/threonine phosphorylation of the adaptor protein, Gab-1 (Grb2-associated binder-1). Phosphorylated Gab-1 promotes PI 3-kinase recruitment to CD44v3. Subsequently, PI 3-kinase is activated (in particular, alpha, beta, gamma forms but not the delta form of the p110 catalytic subunit), AKT signaling occurs, the cytokine (macrophage-colony stimulating factor (M-CSF)) is produced, and tumor cell-specific phenotypes (e.g. tumor cell growth, survival and invasion) are up-regulated. Our results also demonstrate that HA/CD44-mediated oncogenic events (e.g. AKT activation, M-CSF production and breast tumor cell-specific phenotypes) can be effectively blocked by a PI 3-kinase inhibitor (LY294002). Finally, we have found that overexpression of a dominant-negative form of ROK (by transfection of MBA-MD-231 cells with the Rho-binding domain cDNA of ROK) not only inhibits HA/CD44-mediated RhoA-ROK activation and Gab-1 phosphorylation but also down-regulates oncogenic signaling events (e.g. Gab-1.PI 3-kinase-CD44v3 association, PI 3-kinase-mediated AKT activation, and M-CSF production) and tumor cell behaviors (e.g. cell growth, survival, and invasion). Taken together, these findings strongly suggest that CD44 interaction with p115RhoGEF and ROK plays a pivotal role in promoting Gab-1 phosphorylation leading to Gab-1.PI 3-kinase membrane localization, AKT signaling, and cytokine (M-CSF) production during HA-mediated breast cancer progression.
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PMID:Hyaluronan-mediated CD44 interaction with RhoGEF and Rho kinase promotes Grb2-associated binder-1 phosphorylation and phosphatidylinositol 3-kinase signaling leading to cytokine (macrophage-colony stimulating factor) production and breast tumor progression. 1274 84

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. However, the specific RhoGEF that translates CXCR4 signaling into RhoA activity and cell motility is unknown. We screened the three regulator of G-protein signaling RhoGEFs (LSC, LARG and PRG) and found that PRG selectively regulated the migration and invasion of CXCR4-overexpressing breast tumor cells. Interestingly, we found that PDZ-RhoGEF (PRG) was required for spatial organization of F-actin structures in the center, but not periphery of the cells. The effects on the cytoskeleton were mirrored by the spatial effects on RhoA activity that were dependent upon PRG. Loss of PRG also enhanced adherens junctions in the epithelial-like MCF7-CXCR4 cell line, and inhibited directional persistence and polarity in the more mesenchymal MDA-MB-231 cell line. Thus, PRG is essential for CXCR4-driven tumor cell migration through spatial regulation of RhoA and the subsequent organization of the cytoskeletal structures that support motility. Furthermore, immunohistochemical analysis of human breast tumor tissues shows a significant increase of PRG expression in the invasive areas of the tumors, suggesting that this RhoGEF is associated with breast tumor invasion in vivo.
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PMID:PDZ-RhoGEF is essential for CXCR4-driven breast tumor cell motility through spatial regulation of RhoA. 2386 72