The concentration of low‐density lipoprotein (LDL) cholesterol (C) in plasma is a key determinant of cardiovascular disease risk and human genetic studies have long endeavoured to elucidate the pathways that regulate LDL metabolism. Massive genome‐wide association studies (GWASs) of common genetic variation associated with LDL‐C in the population have implicated SORT1 in LDL metabolism. Using experimental paradigms and standards appropriate for understanding the mechanisms by which common variants alter phenotypic expression, three recent publications have presented divergent and even contradictory findings. (...) Interestingly, although these reports each linked SORT1 to LDL metabolism, they did not agree on a mechanism to explain the association. Here, we review recent mechanistic studies of SORT1 – the first gene identified by GWAS as a determinant of plasma LDL‐C to be evaluated mechanistically. (shrink)

The common neurotrophin receptor (p75NTR) regulates various functions in the developing and adult nervous system. Cell survival, cell death, axonal and growth cone retraction, and regulation of the cell cycle can be regulated by p75NTR‐mediated signals following activation by either mature or pro‐neurotrophins and in combination with various co‐receptors, including Trk receptors and sortilin. Here, we review the known functions of p75NTR by cell type, receptor‐ligand combination, and whether regulated intra‐membrane proteolysis of p75NTR is required for signalling. We highlight (...) that the generation of the intracellular domain fragment of p75NTR is associated with many of the receptor functions, regardless of its ligand and co‐receptor interactions. (shrink)

The common neurotrophin receptor (p75NTR) regulates various functions in the developing and adult nervous system. Cell survival, cell death, axonal and growth cone retraction, and regulation of the cell cycle can be regulated by p75NTR‐mediated signals following activation by either mature or pro‐neurotrophins and in combination with various co‐receptors, including Trk receptors and sortilin. Here, we review the known functions of p75NTR by cell type, receptor‐ligand combination, and whether regulated intra‐membrane proteolysis of p75NTR is required for signalling. We highlight (...) that the generation of the intracellular domain fragment of p75NTR is associated with many of the receptor functions, regardless of its ligand and co‐receptor interactions. (shrink)

Neurotrophins are a small family of dimeric secretory proteins in vertebrate neurons with a broad spectrum of functions. They are generated as pro‐proteins with a functionality that is distinct from the proteolytically processed form. The cellular responses of neurotrophins are mediated by three different types of receptor proteins, the receptor tyrosine kinases of the Trk family, the neurotrophin receptor p75NTR, which is a member of the tumor necrosis factor receptor (TNFR) superfamily, and sortilin, previously characterized as neurotensin receptor. Recent (...) studies have revealed an intriguing pattern: neurotrophins can elicit opposing signals utilising their variable configuration and different receptor types. BioEssays 28: 583–594, 2006. © 2006 Wiley Periodicals, Inc. (shrink)