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Highlights
HIGHLIGHTS Volume 312, Number 7, April 15, 2006 Silencing of LASP-1 influences zyxin localization, inhibits proliferation and reduces migration in breast cancer cells. By Thomas G.P. Grunewald, Ulrike Kammerer, Detlef Schindler, Arnd Honig, Michael Zimmer and Elke Butt . . 974 Breast cancer is the most common cause of cancer among women in western countries. Approximately 8 in 100 women will develop breast cancer at some stage in their life. A recently identified LIM and SH3 protein (LASP-1) was found to be expressed in all tissue samples of invasive ductal carcinoma tested, while benign ducti were negative for LASP-1. Using small interfering RNA to knockdown LASP-1 expression in breast cancer cells, we demonstrated that LASP-1 promotes cell motility and proliferation - most likely through the regulation of zyxin localisation. The critical role of LASP-1 in breast cancer metastasis and its strong correlation with malign tissue suggests this protein to be a specific diagnostic marker for breast cancer prognosis.
Dissociation of ERK and Akt signaling in endothelial cell angiogenic responses to B-amyloid. By Jordi Magrane, Rial A. Christensen, Kenneth M. Rosen, Vimal Veereshwarayya and Henry W. Querfurth . . . . . . . . . . . . . . . . . . . . 996 h-Amyloid peptides are toxic to many cell signal and homeostatic processes under experimental conditions. The relative importance of these biochemical events may be ordered by correlations with tests of specialized cell function. The effectiveness of synaptic transmission and contraction are appropriate ‘‘read-outs’’ for neuronal and muscle systems. Another structure affected by amyloid deposits is the cerebral blood vessel. Endothelial proliferation and migration were chosen by the authors to study the functional significance for angiogenesis of Ah stress on two classical signal pathways. The authors show that sublethal doses of extracellular h-amyloid inhibit the MAPK/ERK path, probably at the VEGF-receptor level. The effect was correlated with a decline in migration. The PI3K/Akt cascade was not affected. On the other hand, intracellular Ah-expression reduces both Akt activation and cell survival, but not ERK. This double dissociation would predict that separate strategies to neutralize the effects of extra and intracellular pools of Ah may be necessary in Alzheimer’s disease and amyloid angiopathy.
SUMO modification through rapamycin-mediated heterodimerization reveals a dual role for Ubc9 in targeting RanGAP1 to nuclear pore complexes. By Shanshan Zhu, Hong Zhang and Michael J. Matunis . . . . . . . . . 1042 Proteins involved in a variety of essential cellular processes are post-translationally regulated by SUMO modification. The effects of SUMO modification on many proteins, however, remain poorly understood due to limitations in the ability to specifically manipulate their modification in vivo. This article describes a novel approach for affecting the SUMO modification and demodification of individual proteins using the rapamycin heterodimerization system. By fusing rapamycin-binding domains to RanGAP1 and SUMO-1, it was demonstrated that rapamycin-mediated heterodimerization mimics the effects of covalent SUMO-1 modification. This system was used to elucidate the mechanism by which SUMO-1 modification targets RanGAP1 to nuclear pore complexes. The findings demonstrate that rapamycin-mediated heterodimerization is a powerful new approach for investigating the effects of SUMO modification in vivo.
Rin1 regulates insulin receptor signal transduction pathways. By C.M. Hunker, H. Giambini, A. Galvis, J. Hall, I. Kruk, M.L. Veisaga and M.A. Barbieri . . 1106 Initial studies have identified Ras interaction/interference 1 (Rin1) as a Ras binding protein based on the properties of its carboxyl-terminal domain. Recent studies demonstrated that Rin1 regulates epidermal growth factor receptor-mediated endocytosis. Interestingly, Rin1 has all of the characteristics necessary to facilitate endocytosis of and signaling from activated insulin receptor: an SH2 domain, a Ras binding domain and a Rab5 GEF domain. The present study by Hunker et al. reveals that Rin1 regulates the rate of insulin receptor-mediated endocytosis, insulin-stimulated growth as well as activation of Akt and Erk1/2 kinases. Moreover, we demonstrate that Rin1 also regulates signaling pathways involved in the stimulation of glucogen synthesis by insulin. Thus, Rin1 plays an essential role in insulin receptor trafficking, signaling and insulin action.
Dissociation of ERK and Akt signaling in endothelial cell angiogenic responses to B-amyloid. By Jordi Magrane, Rial A. Christensen, Kenneth M. Rosen, Vimal Veereshwarayya and Henry W. Querfurth . . . . . . . . . . . . . . . . . . . . 996 h-Amyloid peptides are toxic to many cell signal and homeostatic processes under experimental conditions. The relative importance of these biochemical events may be ordered by correlations with tests of specialized cell function. The effectiveness of synaptic transmission and contraction are appropriate ‘‘read-outs’’ for neuronal and muscle systems. Another structure affected by amyloid deposits is the cerebral blood vessel. Endothelial proliferation and migration were chosen by the authors to study the functional significance for angiogenesis of Ah stress on two classical signal pathways. The authors show that sublethal doses of extracellular h-amyloid inhibit the MAPK/ERK path, probably at the VEGF-receptor level. The effect was correlated with a decline in migration. The PI3K/Akt cascade was not affected. On the other hand, intracellular Ah-expression reduces both Akt activation and cell survival, but not ERK. This double dissociation would predict that separate strategies to neutralize the effects of extra and intracellular pools of Ah may be necessary in Alzheimer’s disease and amyloid angiopathy.
SUMO modification through rapamycin-mediated heterodimerization reveals a dual role for Ubc9 in targeting RanGAP1 to nuclear pore complexes. By Shanshan Zhu, Hong Zhang and Michael J. Matunis . . . . . . . . . 1042 Proteins involved in a variety of essential cellular processes are post-translationally regulated by SUMO modification. The effects of SUMO modification on many proteins, however, remain poorly understood due to limitations in the ability to specifically manipulate their modification in vivo. This article describes a novel approach for affecting the SUMO modification and demodification of individual proteins using the rapamycin heterodimerization system. By fusing rapamycin-binding domains to RanGAP1 and SUMO-1, it was demonstrated that rapamycin-mediated heterodimerization mimics the effects of covalent SUMO-1 modification. This system was used to elucidate the mechanism by which SUMO-1 modification targets RanGAP1 to nuclear pore complexes. The findings demonstrate that rapamycin-mediated heterodimerization is a powerful new approach for investigating the effects of SUMO modification in vivo.
Rin1 regulates insulin receptor signal transduction pathways. By C.M. Hunker, H. Giambini, A. Galvis, J. Hall, I. Kruk, M.L. Veisaga and M.A. Barbieri . . 1106 Initial studies have identified Ras interaction/interference 1 (Rin1) as a Ras binding protein based on the properties of its carboxyl-terminal domain. Recent studies demonstrated that Rin1 regulates epidermal growth factor receptor-mediated endocytosis. Interestingly, Rin1 has all of the characteristics necessary to facilitate endocytosis of and signaling from activated insulin receptor: an SH2 domain, a Ras binding domain and a Rab5 GEF domain. The present study by Hunker et al. reveals that Rin1 regulates the rate of insulin receptor-mediated endocytosis, insulin-stimulated growth as well as activation of Akt and Erk1/2 kinases. Moreover, we demonstrate that Rin1 also regulates signaling pathways involved in the stimulation of glucogen synthesis by insulin. Thus, Rin1 plays an essential role in insulin receptor trafficking, signaling and insulin action.