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Rap1 Activation (rap1 + activation)
Selected AbstractsRole of the Rap1 GTPase in astrocyte growth regulationGLIA, Issue 3 2003Anthony J. Apicelli Abstract Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome in which affected individuals develop nervous system abnormalities that might reflect astrocyte dysfunction. The TSC2 gene product, tuberin, encodes a GTPase-activating protein (GAP) domain, which regulates the activity of Rap1 in vitro. To determine whether dysregulated Rap1, resulting from TSC2 inactivation, leads to increased astrocyte proliferation in vivo, we generated transgenic mice expressing activated Rap1G12V specifically in astrocytes. We observed no statistically significant difference in the number of astrocytes between wild-type and GFAP-Rap1G12V littermates in vivo; however, during log-phase growth, we observed a 25% increase in GFAP-Rap1G12V astrocyte doubling times compared to wild-type controls. This decreased proliferation was associated with delayed MAP kinase, but not AKT, activation. Lastly, to determine whether constitutive Rap1 activation could reverse the increased astrocyte proliferation observed in transgenic mice expressing oncogenic RasG12V, we generated transgenic mice expressing both RasG12V and Rap1G12V in astrocytes. These double transgenic mice showed a striking reversion of the RasG12V astrocyte growth phenotype. Collectively, these results argue that the tumor suppressor properties of tuberin are unlikely to be related to Rap1 inactivation and that Rap1 inhibits mitogenic Ras pathway signaling in astrocytes. GLIA 42:225,234, 2003. © 2003 Wiley-Liss, Inc. [source] Rap1 and p38 MAPK mediate 8-chloro-cAMP-induced growth inhibition in mouse fibroblast DT cellsJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2006Young-Ho Ahn 8-Cl-cAMP, which is known to induce differentiation, growth inhibition, and apoptosis in various cancer cells, has been investigated as a putative anti-cancer drug. Previously, we reported that 8-Cl-cAMP and its metabolite 8-Cl-adenosine induce growth inhibition and apoptosis through p38 mitogen-activated protein kinase (MAPK) activation. To further investigate the signal mechanisms that regulate the cellular effects of 8-Cl-cAMP, we focused on a small GTPase Rap1 that is known to be involved in growth inhibition and reverse-transformation. 8-Cl-cAMP and 8-Cl-adenosine could increase Rap1 activity, which was blocked by ABT702,an adenosine kinase inhibitor. This suggests that 8-Cl-cAMP-induced Rap1 activation is also dependent on the metabolic degradation of 8-Cl-cAMP. Overexpression of a constitutively active mutant form of Rap1 (Rap1V12) attenuated cellular growth and soft-agar colony formation, which was basically the same effect as that observed with the 8-Cl-cAMP treatment. Furthermore, the Rap1V12 transfectant showed a high level of p38 MAPK activation. However, 8-Cl-cAMP-induced Rap1 activation was not diminished by SB203580, a p38 MAPK inhibitor, suggesting that Rap1 activation might act upstream of p38 MAPK activation during 8-Cl-cAMP-induced growth inhibition. J. Cell. Physiol. 209: 1039,1045, 2006. © 2006 Wiley-Liss, Inc. [source] More PKA independent ,-adrenergic signalling via cAMP: Is Rap1-mediated glucose uptake in vascular smooth cells physiologically important?BRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2007J Jensen The proteome characterising a specific cell type makes up a unique intracellular signalling network and signalling has to be studied in a cell specific manner. ,-Adrenergic receptors are coupled to production of cAMP and PKA was initially believed to be the only protein activated by cAMP. However, cAMP-mediated signalling via Epac and Rap1 has emerged as an important contributor to cAMP signalling. In the current issue of the British Journal of Pharmacology, Kanda and Watanabe report that adrenaline stimulates glucose uptake in vascular smooth muscle cells. With pharmacological methods, supplemented with small interfering RNA against Rap1, the authors demonstrate that adrenaline increases glucose uptake via Gs, adenylate cyclase, cAMP and Rap1 activation. The authors could document neither PKA nor Epac as the receptor for cAMP mediating the effect. Although there is no doubt that Rap1 mediates adrenaline-stimulated glucose uptake in vascular smooth muscle cells, it may be too early to exclude PKA and Epac. British Journal of Pharmacology (2007) 151, 423,425; doi:10.1038/sj.bjp.0707248 [source] | ||||||||||