Signal transduction

About: Signal transduction is a research topic. Over the lifetime, 122628 publications have been published within this topic receiving 8209258 citations. The topic is also known as: GO:0007165.

Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo.

Abstract: The pro-inflammatory cytokine interleukin (IL)-6 (refs. 1-5) can bind to cells lacking the IL-6 receptor (IL-6R) when it forms a complex with the soluble IL-6R (sIL-6R) (trans signaling). Here, we have assessed the contribution of this system to the increased resistance of mucosal T cells against apoptosis in Crohn disease (CD), a chronic inflammatory disease of the gastrointestinal tract. A neutralizing antibody against IL-6R suppressed established experimental colitis in various animal models of CD mediated by type 1 T-helper cells, by inducing apoptosis of lamina propria T cells. Similarly, specific neutralization of sIL-6R in vivo by a newly designed gp130-Fc fusion protein caused suppression of colitis activity and induction of apoptosis, indicating that sIL-6R prevents mucosal T-cell apoptosis. In patients with CD, mucosal T cells showed strong evidence for IL-6 trans signaling, with activation of signal transducer and activator of transcription 3, bcl-2 and bcl-xl. Blockade of IL-6 trans signaling caused T-cell apoptosis, indicating that the IL-6-sIL-6R system mediates the resistance of T cells to apoptosis in CD. These data indicate that a pathway of T-cell activation driven by IL-6-sIL-6R contributes to the perpetuation of chronic intestinal inflammation. Specific targeting of this pathway may be a promising new approach for the treatment of CD.

The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins

Abstract: Two glucose-regulated proteins, GRP78 and GRP94, are major constituents of the endoplasmic reticulum (ER) of mammalian cells. These proteins are synthesized constitutively in detectable amounts under normal growth conditions; they can also be induced under a variety of conditions of stress including glucose starvation and treatment with drugs that inhibit cellular glycosylation, with calcium ionophores or with amino-acid analogues. Unlike the closely-related heat shock protein (HSP) family, the GRPs are not induced significantly by high temperature. Recently, GRP78 has been identified as the immunoglobulin heavy chain binding protein (BiP) (ref. 5 and Y.K. et al., in preparation) which binds transiently to a variety of nascent, wild-type secretory and transmembrane proteins and permanently to malfolded proteins that accumulate within the ER. We have tested the hypothesis that the presence of malfolded proteins may be the primary signal for induction of GRPs by expressing wild-type and mutant forms of influenza virus haemagglutinin (HA) in simian cells. Only malfolded HAs, whose transport from the ER is blocked, induced the synthesis of GRPs 78 and 94. Additional evidence is presented that malfolding per se, rather than abnormal glycosylation, is the proximal inducer of this family of stress proteins.

Functions of sphingolipids and sphingolipid breakdown products in cellular regulation

Abstract: The discovery that breakdown products of cellular sphingolipids are biologically active has generated interest in the role of these molecules in cell physiology and pathology. Sphingolipid breakdown products, sphingosine and lysosphingolipids, inhibit protein kinase C, a pivotal enzyme in cell regulation and signal transduction. Sphingolipids and lysosphingolipids affect significant cellular responses and exhibit antitumor promoter activities in various mammalian cells. These molecules may function as endogenous modulators of cell function and possibly as second messengers.

Regulation of development and differentiation by the extracellular matrix

Abstract: Differentiation is a continuously regulated process and interactions between the cell and its environment play a major role in maintaining stable expression of differentiation specific genes (Blau and Baltimore, 1991). An important component of the cellular environment is the extracel-lular matrix (ECM), which is composed of glycoproteins, proteoglycans and glycosaminoglycans that are secreted and assembled locally into an organised network to which cells adhere (Hay, 1981). An ECM is present within mam-malian embryos from the two-cell stage and is a component of the environment of all cell types, although the composition of the ECM and the spatial relationships between cells and ECM differ between tissues. Cells may be completely surrounded by ECM, as is the case for chondrocytes, or may contact the ECM only at one surface, as exemplified by epithelial and endothelial cells. In some tissues only a proportion of the cells are exposed to ECM: for example , in stratified epithelia. The ECM offers structural support for cells, and can also act as a physical barrier or selective filter to soluble molecules. It has been clear for many years (Grobstein, 1954; Bis-sell et al., 1982) that the ECM plays a role in regulating the differentiated phenotype of cells (reviewed by Watt, 1986), but the mechanisms involved remained largely mysterious until recently, when cell-binding sites within individual ECM glycoproteins and specific ECM receptors were identified. The cell-binding sites were mapped by using pro-teolytic fragments and synthetic peptides to define the minimal sequences responsible for adhesive activity. In the case of fibronectin, the primary determinant of cell-binding activity for many cell types resides in the sequence GRGDSP, which occurs in one of the type III repeats that form the central domain of the molecule (Ruoslahti and Pierschbacher, 1987). Subsequently, RGD-containing sequences have been found in other matrix proteins, and additional short linear adhesive sequence motifs have been defined, although it is clear that the three-dimensional structure of matrix proteins is also an important determinant of adhesive activity (reviewed by Humphries, 1990). Affinity chromatography techniques, together with adhesion-perturbing antibodies that recognise specific plasma membrane glycoproteins, allowed the identification of ECM receptors, many of which belong to the integrin family of α/β het-erodimers (Ruoslahti and Pierschbacher, 1987; Hynes, 1987). In this review, we will summarise some of the evidence that ECM components regulate differentiation and development , describe the regulatory mechanisms involved and, finally, discuss the intracellular events that may transduce signals …