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Signalling Properties (signalling + property)

Distribution by Scientific Domains

Medical Sciences	75%

Selected Abstracts

Genetic variants of insulin receptor substrate-1 (IRS-1) in syndromes of severe insulin resistance.

DIABETIC MEDICINE, Issue 10 2002
Functional analysis of Ala513Pro, Gly1158Glu IRS-
Abstract Aims To define further the role of IRS-1 mutations in human syndromes of severe insulin resistance. Methods The IRS-1 gene was scanned for mutations in 83 unrelated affected subjects and 47 unaffected individuals using fluorescent single-strand conformation polymorphism (fSSCP) analysis. A novel heterozygous mutation, Gly1158Glu, was found in one affected subject. Four and two subjects were heterozygous for the previously reported variants Gly972Arg and Ala513Pro, respectively. The previously identified variant Gly819Arg was found in one affected and one unaffected subject. While Gly972Arg has been described to alter the signalling properties of IRS-1, no functional studies of Ala513Pro or Gly1158Glu have been reported. Results Chinese hamster ovary (CHO) cells stably over-expressing the insulin receptor were transiently transfected with vectors expressing either wild-type, Glu1158 or Pro513 IRS-1. A modest increase in insulin-stimulated tyrosine phosphorylation of Glu1158 IRS-1 was observed. However, this did not result in any significant change in the association of Grb2 or the p85, subunit of PI3-kinase or of PI3-kinase activity. In parallel studies, the Pro513 IRS-1 variant was indistinguishable from wild-type IRS-1. Conclusions While subtle effects of these variants cannot be excluded in this system, it is unlikely that these variants are responsible for the extreme insulin resistance seen in the subjects harbouring them. Although IRS proteins play a central role in insulin signalling, functionally significant mutations in the IRS-1 gene are a rare cause of human syndromes of severe insulin resistance. [source]

Rapid induction of apoptosis in B-cell lymphoma by functionally isolated human antibodies

INTERNATIONAL JOURNAL OF CANCER, Issue 2 2006
Johan Fransson
Abstract Novel panning and screening methodology was devised to isolate high affinity human recombinant scFv antibody fragments with functionally associated properties in B lymphoma cells. The approach was used to generate a panel of apoptosis-inducing antibodies specific for antigens differentially expressed in B lymphoma vs. T leukaemia cells. The selections resulted in an antibody pool with near perfect selectivity (>99%) for the B lymphoma target cells. Randomly picked clones (72) revealed 7 unique antibody genotypes. Six of these rapidly induced apoptosis in target cells. Following the conversion to full IgGs, the antibodies were shown to be specific for HLA-DR/DP, the B-cell receptor , chain and for CD54/ICAM-1. The latter receptor was not previously associated with apoptotic properties in B-cell lymphomas. Anti-ICAM-1 IgG induced apoptosis in a broad range of B lymphoma cell lines and were shown by immunohistochemistry to bind strongly to B lymphoma tissue obtained from 5 different B lymphoma patients. The recombinant IgG antibodies had affinities in the subnanomolar (0.3 nM) to nanomolar (3 nM) range. The described technology is generally applicable for the rapid isolation of high affinity human antibodies with specificity for differentially expressed cell surface receptors with intrinsic negative or positive signalling properties from naïve phage libraries. © 2006 Wiley-Liss, Inc. [source]

Nociceptive and behavioural sensitisation by protein kinase C, signalling in the CNS

JOURNAL OF NEUROCHEMISTRY, Issue 1 2008
Kristof Van Kolen
Abstract Despite the apparent homology in the protein kinase C (PKC) family, it has become clear that slight structural differences are sufficient to have unique signalling properties for each individual isoform. For PKC, in depth investigation of these aspects revealed unique actions in the CNS and lead to development of specific modulators with clinical perspective. In this review, we describe to which extent PKC, is distinct from other isoforms on the level of tissue expression and protein structure. As this kinase is highly expressed in the brain, we outline three main aspects of PKC, signalling in the CNS. First, its ability to alter the permeability of N-type Ca2+ channels in dorsal root ganglia has been shown to enhance nociception. Secondly, PKC, increases anxiety by diminishing GABAAR-induced inhibitory post-synaptic currents in the prefrontal cortex. Another important aspect of the latter inhibition is the reduced sensitivity of GABAA receptors to ethanol, a mechanism potentially contributing to abuse. A third signalling cascade improves cognitive functions by facilitating cholinergic signalling in the hippocampus. Collectively, these findings point to a physical and behavioural sensitising role for this kinase. [source]

G-protein-coupled receptor phosphorylation: where, when and by whom

BRITISH JOURNAL OF PHARMACOLOGY, Issue S1 2008
A B Tobin
Almost all G-protein coupled receptors (GPCRs) are regulated by phosphorylation and this process is a key event in determining the signalling properties of this receptor super-family. Receptors are multiply phosphorylated at sites that can occur throughout the intracellular regions of the receptor. This diversity of phospho-acceptor sites together with a lack of consensus phosphorylation sequences has led to the suggestion that the precise site of phosphorylation is not important in the phosphorylation-dependent regulation of GPCR function but rather it is the increase in bulk negative charge of the intracellular face of the receptor which is the significant factor. This review investigates the possibility that the multi-site nature of GPCR phosphorylation reflects the importance of specific phosphorylation events which mediate distinct signalling outcomes. In this way receptor phosphorylation may provide for a flexible regulatory mechanism that can be tailored in a tissue specific manner to regulate physiological processes. By understanding the flexible nature of GPCR phosphorylation if may be possible to develop agonists or allosteric modulators that promote a subset of phosphorylation events on the target GPCR and thereby restrict the action of the drug to a particular receptor mediated signalling response. British Journal of Pharmacology (2008) 153, S167,S176; doi:10.1038/sj.bjp.0707662; published online 14 January 2008 [source]