Biomedical subjects

Terence E Ryan

Publications and source records attributed to Terence E Ryan.

7 recordsLinked to original sources

PubMed2002

Proteomics: drug target discovery on an industrial scale.

The discovery of targets that are sufficiently robust to yield marketable therapeutics is an enormous challenge. Through the years, several approaches have been used with varying degrees of success. These include target-independent screening of tumor-derived cell lines (disease-dependent), reductionist approaches to identifying crucial elements of disease-affected pathways, disease-independent screening of homologs of previously drugged targets, disease-dependent 'global' examination of gene transcript levels, and disease-dependent global examination of protein expression levels. These endeavors have been enabled by several major advancements in technology, most recently, the sequencing of the human genome. This review identifies the technical issues to be addressed for industrial-scale protein-based discovery in the identification of targets for therapeutic (or diagnostic) intervention. Such approaches aim to direct discovery in a way that increases the probability of robust target identification, and decreases the probability of failure owing to variable expression in this emerging field.

Algorithms↗

PubMed2002

Enabling parallel protein analysis through mass spectrometry.

The targets of the majority of drugs on the market and in development are proteins, and the efficient analysis of these molecules is critical to defining targets for better therapeutic intervention. Mass spectrometry is currently the key technology for parallel protein analysis (also referred to as proteomics). In this review we will describe recent advances in mass spectrometry instrumentation, methods and applications that are likely to impact drug discovery.

Animals↗

PubMed1997

An orphan receptor tyrosine kinase family whose members serve as nonintegrin collagen receptors.

Mammalian cells constantly monitor and respond to a myriad of extracellular signals, often by using cell surface receptors. Two important classes of cell surface receptors include the receptor tyrosine kinases, which recognize peptide growth factors such as insulin, and the integrins, which most often mediate binding to components of the extracellular matrix. We report that the collagens serve as ligands for the previously orphan family of discoidin domain-containing receptor-like tyrosine kinases. The unexpected realization that an extracellular matrix molecule can directly serve as a ligand for receptor tyrosine kinases provides an example of ligands shared by integrins and receptor tyrosine kinases, and this finding seems likely to change prevailing views about the mechanisms by which cells perceive and respond to the extracellular matrix.

Animals↗

PubMed1996

Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning.

TIE2 is a receptor-like tyrosine kinase expressed almost exclusively in endothelial cells and early hemopoietic cells and required for the normal development of vascular structures during embryogenesis. We report the identification of a secreted ligand for TIE2, termed Angiopoietin-1, using a novel expression cloning technique that involves intracellular trapping and detection of the ligand in COS cells. The structure of Angiopoietin-1 differs from that of known angiogenic factors or other ligands for receptor tyrosine kinases. Although Angiopoietin-1 binds and induces the tyrosine phosphorylation of TIE2, it does not directly promote the growth of cultured endothelial cells. However, its expression in close proximity with developing blood vessels implicates Angiopoietin-1 in endothelial developmental processes.

Amino Acid Sequence↗

PubMed1996

Agrin acts via a MuSK receptor complex.

Formation of th neuromuscular junction depends upon reciprocal inductive interactions between the developing nerve and muscle, resulting in the precise juxtaposition of a differentiated nerve terminal with a highly specialized patch on the muscle membrane, termed the motor endplate. Agrin is a nerve-derived factor that can induced molecular reorganizations at the motor endplate, but the mechanism of action of agrin remains poorly understood. MuSK is a receptor tyrosine kinase localized to the motor endplate, seemingly well positioned to receive a key nerve-derived signal. Mice lacking either agrin or MuSK have recently been generated and exhibit similarly profound defects in their neuromuscular junctions. Here we demonstrate that agrin acts via a receptor complex that includes MuSK as well as a myotube-specific accessory component.

Agrin↗

PubMed1996

Eph receptors and ligands comprise two major specificity subclasses and are reciprocally compartmentalized during embryogenesis.

We report that the many Eph-related receptor tyrosine kinases, and their numerous membrane-bound ligands, can each be grouped into only two major specificity subclasses. Receptors in a given subclass bind most members of a corresponding ligand subclass. The physiological relevance of these groupings is suggested by viewing the collective distributions of all members of a subclass. These composite distributions, in contrast with less informative patterns seen with individual members of the family, reveal that the developing embryo is subdivided into domains defined by reciprocal and apparently mutually exclusive expression of a receptor subclass and its corresponding ligands. Receptors seem to encounter their ligands only at the interface between these domains. This reciprocal compartmentalization implicates the Eph family in the formation of spatial boundaries that may help to organize the developing body plan.

Animals↗

PubMed1995

The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptor tyrosine kinases.

We report the identification of ligands for Tyro 3 (alternatively called Sky, rse, brt, or tif) and Axl (alternatively, Ark or UFO), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein S, a protease regulator that is a potent anticoagulant, and Gas6, a protein related to protein S but lacking any known function. Our results are reminiscent of recent findings that the procoagulant thrombin, a protease that drives clot formation by cleaving fibrinogen to form fibrin, also binds and activates intracellular signaling via a G protein-coupled cell surface receptor. Proteases and protease regulators that also activate specific cell surface receptors may serve to integrate coagulation with associated cellular responses required for tissue repair and growth, as well as to coordinate protease cascades and associated cellular responses in other systems, such as those involved in growth and remodeling of the nervous system.

3T3 Cells↗