Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP

Raf-1 phosphorylates and activates MEK-1, a kinase that activates the extracellular signal regulated kinases (ERK). This kinase cascade controls the proliferation and differentiation of different cell types. Here we describe a Raf-1-interacting protein, isolated using a yeast two-hybrid screen. This protein inhibits the phosphorylation and activation of MEK by Raf-1 and is designated RKIP (Raf kinase inhibitor protein). In vitro, RKIP binds to Raf-1, MEK and ERK, but not to Ras. RKIP co-immunoprecipitates with Raf-1 and MEK from cell lysates and colocalizes with Raf-1 when examined by confocal microscopy. RKIP is not a substrate for Raf-1 or MEK, but competitively disrupts the interaction between these kinases. RKIP overexpression interferes with the activation of MEK and ERK, induction of AP-1-dependent reporter genes and transformation elicited by an oncogenically activated Raf-1 kinase. Downregulation of endogenous RKIP by expression of antisense RNA or antibody microinjection induces the activation of MEK-, ERK- and AP-1-dependent transcription. RKIP represents a new class of protein-kinase-inhibitor protein that regulates the activity of the Raf/MEK/ERK modul

Differential alphav integrin-mediated Ras-ERK signaling during two pathways of angiogenesis.

Antagonists of alphavbeta3 and alphavbeta5 disrupt angiogenesis in response to bFGF and VEGF, respectively. Here, we show that these alphav integrins differentially contribute to sustained Ras-extracellular signal-related kinase (Ras-ERK) signaling in blood vessels, a requirement for endothelial cell survival and angiogenesis. Inhibition of FAK or alphavbeta5 disrupted VEGF-mediated Ras and c-Raf activity on the chick chorioallantoic membrane, whereas blockade of FAK or integrin alphavbeta3 had no effect on bFGF-mediated Ras activity, but did suppress c-Raf activation. Furthermore, retroviral delivery of active Ras or c-Raf promoted ERK activity and angiogenesis, which anti-alphavbeta5 blocked upstream of Ras, whereas anti-alphavbeta3 blocked downstream of Ras, but upstream of c-Raf. The activation of c-Raf by bFGF/alphavbeta3 not only depended on FAK, but also required p21-activated kinase-dependent phosphorylation of serine 338 on c-Raf, whereas VEGF-mediated c-Raf phosphorylation/activation depended on Src, but not Pak. Thus, integrins alphavbeta3 and alphavbeta5 differentially regulate the Ras-ERK pathway, accounting for distinct vascular responses during two pathways of angiogenesis

Inclusion ideals and inclusion problems: Parsons and Luhmann on religion and secularization

This paper builds upon the theoretical work of Talcott Parsons and Niklas Luhmann and offers a critical reconstruction of their views on religion (Christianity) and secularization in the western world. It discusses the relation between the functional differentiation of modern society, the individualization of inclusion imperatives and the changing expectations regarding inclusion/exclusion in religious communication. From this perspective, it analyzes secularization in terms of perceived problems of inclusion in religious communication, and in terms of the reactions of Christian religions to these perceived problems. It thereby shows how the theories of Parsons and Luhmann are useful for empirical and historical research, and how they open up new perspectives for empirical and historical research

Locally inertial null normal coordinates

Locally inertial coordinates are constructed by carrying Riemann normal coordinates on a codimension two spacelike surface along the geodesics normal to it. Since the normal tangents are labelled by components with respect to a null basis, these coordinates are referred to as null normal coordinates. They are convenient in the study of local causal horizons. As an application, the coordinate system is used to specify a vector field that satisfies the Killing equation approximately in a small region and the Killing identity exactly on a single null geodesic. We also construct a vector field on a surface, starting from a vector at a given point on the surface. This construction may be regarded as a generalisation of the notion of Fermi-Walker transport.Comment: 9 pages, 1 figur

Toric systems and mirror symmetry

Hille and Perling associate to every cyclic full strongly exceptional sequence of line bundles on a toric weak Fano surface a toric system, which defines a new toric surface. In this note we interprete this construction as an instance of mirror symmetry and extend it to a duality on the set toric weak Fano surfaces equiped with a cyclic full strongly exceptional sequence