LyGDl functions in cancer metastasis by anchoring Rho proteins to the cell membrane
MOLECULAR CARCINOGENESIS
Authors: Ota, T; Maeda, M; Suto, S; Tatsuka, M
Abstract
Rho family GTPases play an important role in a number of processes related to metastasis, and RhoGDP dissociation, inhibitors (RhoGDIs) regulate Rho family proteins. We cloned genomic DNA from colon carcinoma SW480 cells capable of transforming nonmetastatic ras-transformed 1-1ras1000 cells into metastatic cells. This DNA contained a truncated human ras homolog gene family GDP dissociation inhibitor beta (ARHGDIB) gene, resulting in a C-terminal truncated form of LyGDI (DeltaC-LyGDI, 166-201 deletion), a member of the RhoGDIs. The stable expression of DeltaC-LyGDI induced pulmonary metastasis in 1-1ras1000 cells, whereas expression of full-length LyGDI did not induce metastasis. DeltaC-LyGDI was preferentially localized in the membrane, detected in a NP-40-insoluble fraction, and co-purified with radixin, moesin, Rac1, Cdc42, and RhoA. In DeltaC-LyGDI transfectant, an activation state of Rac1 was elevated and DeltaC-LyGDI was associated with Rac1-GTP. In keeping with the observed localization of Rac1 to the cell membrane and the elevated level of Rac1-GTP, DeltaC-LyGDI transfectants were found to be more invasive than mock transfectant. These results suggest that LyGDI functions in the cell membrane to afford spatial regulation of Rho family GTPase signaling through ezrin radixin moesin (ERM) proteins during metastasis. (C) 2004 Wiley-Liss, Inc.
Antibodies against ARHGDIB are associated with long-term kidney graft loss
AMERICAN JOURNAL OF TRANSPLANTATION
Authors: Kamburova, Elena G.; Gruijters, Maartje L.; Kardol-Hoefnagel, Tineke; Wisse, Bram W.; Joosten, Irma; Allebes, Wil A.; van der Meer, Arnold; Hilbrands, Luuk B.; Baas, Marije C.; Spierings, Eric; Hack, Cornelis E.; van Reekum, Franka E.; van Zuilen, Arjan D.; Verhaar, Marianne C.; Bots, Michiel L.; Drop, Adriaan C. A. D.; Plaisier, Loes; Melchers, Rowena C. A.; Seelen, Marc A. J.; Sanders, Jan Stephan; Hepkema, Bouke G.; Lambeck, Annechien J. A.; Bungener, Laura B.; Roozendaal, Caroline; Tilanus, Marcel G. J.; Voorter, Christina E.; Wieten, Lotte; van Duijnhoven, Elly M.; Gelens, Marielle A. C. J.; Christiaans, Maarten H. L.; van Ittersum, Frans J.; Nurmohamed, Shaikh A.; Lardy, Neubury M.; Swelsen, Wendy; van der Pant, Karlijn A. M., I; van der Weerd, Neelke C.; ten Berge, Ineke J. M.; Hoitsma, Andries; van der Boog, Paul J. M.; de Fijter, Johan W.; Betjes, Michiel G. H.; Heidt, Sebastiaan; Roelen, Dave L.; Claas, Frans H.; Bemelman, Frederike J.; Otten, Henny G.
Abstract
The clinical significance of non-HLA antibodies on renal allograft survival is a matter of debate, due to differences in reported results and lack of large-scale studies incorporating analysis of multiple non-HLA antibodies simultaneously. We developed a multiplex non-HLA antibody assay against 14 proteins highly expressed in the kidney. In this study, the presence of pretransplant non-HLA antibodies was correlated to renal allograft survival in a nationwide cohort of 4770 recipients transplanted between 1995 and 2006. Autoantibodies against Rho GDP-dissociation inhibitor 2 (ARHGDIB) were significantly associated with graft loss in recipients transplanted with a deceased-donor kidney (N = 3276) but not in recipients of a living-donor kidney (N = 1496). At 10 years after deceased-donor transplantation, recipients with anti-ARHGDIB antibodies (94/3276 = 2.9%) had a 13% lower death-censored covariate-adjusted graft survival compared to the anti-ARHGDIB-negative (3182/3276 = 97.1%) population (hazard ratio 1.82; 95% confidence interval, 1.32-2.53; P = .0003). These antibodies occur independently from donor-specific anti-HLA antibodies (DSA) or other non-HLA antibodies investigated. No significant relations with graft loss were found for the other 13 non-HLA antibodies. We suggest that pretransplant risk assessment can be improved by measuring anti-ARHGDIB antibodies in all patients awaiting deceased-donor transplantation.