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.

Structure of a beta1-adrenergic G-protein-coupled receptor.

Abstract: G-protein-coupled receptors have a major role in transmembrane signalling in most eukaryotes and many are important drug targets. Here we report the 2.7 A resolution crystal structure of a beta(1)-adrenergic receptor in complex with the high-affinity antagonist cyanopindolol. The modified turkey (Meleagris gallopavo) receptor was selected to be in its antagonist conformation and its thermostability improved by earlier limited mutagenesis. The ligand-binding pocket comprises 15 side chains from amino acid residues in 4 transmembrane alpha-helices and extracellular loop 2. This loop defines the entrance of the ligand-binding pocket and is stabilized by two disulphide bonds and a sodium ion. Binding of cyanopindolol to the beta(1)-adrenergic receptor and binding of carazolol to the beta(2)-adrenergic receptor involve similar interactions. A short well-defined helix in cytoplasmic loop 2, not observed in either rhodopsin or the beta(2)-adrenergic receptor, directly interacts by means of a tyrosine with the highly conserved DRY motif at the end of helix 3 that is essential for receptor activation.

Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects

Abstract: Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs) and might provide new therapeutic strategies and reduce side effects.

TGF-ß Signaling in Fibroblasts Modulates the Oncogenic Potential of Adjacent Epithelia

Abstract: Stromal cells can have a significant impact on the carcinogenic process in adjacent epithelia. The role of transforming growth factor-beta (TGF-beta) signaling in such epithelial-mesenchymal interactions was determined by conditional inactivation of the TGF-beta type II receptor gene in mouse fibroblasts (Tgfbr2fspKO). The loss of TGF-beta responsiveness in fibroblasts resulted in intraepithelial neoplasia in prostate and invasive squamous cell carcinoma of the forestomach, both associated with an increased abundance of stromal cells. Activation of paracrine hepatocyte growth factor (HGF) signaling was identified as one possible mechanism for stimulation of epithelial proliferation. Thus, TGF-beta signaling in fibroblasts modulates the growth and oncogenic potential of adjacent epithelia in selected tissues.

Fc RECEPTOR BIOLOGY

Abstract: ▪ Abstract This review deals with membrane Fc receptors (FcR) of the immunoglobulin superfamily. It is focused on the mechanisms by which FcR trigger and regulate biological responses of cells on which they are expressed. FcR deliver signals when they are aggregated at the cell surface. The aggregation of FcR having immunoreceptor tyrosine-based activation motifs (ITAMs) activates sequentially src family tyrosine kinases and syk family tyrosine kinases that connect transduced signals to common activation pathways shared with other receptors. FcR with ITAMs elicit cell activation, endocytosis, and phagocytosis. The nature of responses depends primarily on the cell type. The aggregation of FcR without ITAM does not trigger cell activation. Most of these FcR internalize their ligands, which can be endocytosed, phagocytosed, or transcytosed. The fate of internalized receptor-ligand complexes depends on defined sequences in the intracytoplasmic domain of the receptors. The coaggregation of different FcR result...

Immune inhibitory receptors.

Abstract: With the detailed description and analysis of several inhibitory receptor systems on lymphoid and myeloid cells, a central paradigm has emerged in which the pairing of activation and inhibition is necessary to initiate, amplify, and then terminate immune responses. In some cases, the activating and inhibitory receptors recognize similar ligands, and the net outcome is determined by the relative strength of these opposing signals. The importance of this modulation is demonstrated by the sometimes fatal autoimmune disorders observed in mice with targeted disruption of inhibitory receptors. The significance of these receptors is further evidenced by the conservation of immunoreceptor tyrosine-based inhibitory motifs during their evolution.