RESUMO
Much is known about the pathways that control the biosynthesis, transport and degradation of sphingolipids. During the last two decades, considerable progress has been made regarding the roles this complex group of lipids play in maintaining membrane integrity and modulating responses to numerous signals. Further novel insights have been provided by the analysis of newly discovered genetic diseases in humans as well as in animal models harboring mutations in the genes whose products control sphingolipid metabolism and action. Through the description of the phenotypic consequences of genetic defects resulting in the loss of activity of the many proteins that synthesize, transport, bind, or degrade sphingolipids, this review summarizes the (patho)physiological functions of these lipids.
Assuntos
Erros Inatos do Metabolismo Lipídico/metabolismo , Esfingolipídeos/metabolismo , Animais , Galactosilceramidas/fisiologia , Gangliosídeos/fisiologia , Glucosilceramidas/fisiologia , Humanos , Lactosilceramidas/fisiologia , Lisofosfolipídeos/metabolismo , Camundongos , Transporte Proteico , Receptores de Lisoesfingolipídeo/deficiência , Esfingomielina Fosfodiesterase/deficiência , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Sulfoglicoesfingolipídeos/metabolismoRESUMO
The apelin receptor is a G protein-coupled receptor activated by several apelin fragments. Its tissue distribution suggests that apelin signalling is involved in a broad range of physiological functions. Endothelial cells, which express high levels of apelin receptors, respond to apelin through the phosphorylation of key intracellular effectors associated with cell proliferation and migration. In addition, apelin is a mitogen for endothelial cells and exhibits angiogenic properties in matrigel experiments. This review focuses on the therapeutic potential of apelin signalling, which is associated with pathologies that result from decreased vascularisation (ischemias) or neovascularisation (retinopathies and solid tumors).
Assuntos
Receptores Acoplados a Proteínas G/fisiologia , Transdução de Sinais/fisiologia , Receptores de Apelina , Desenho de Fármacos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Humanos , Neovascularização Patológica/fisiopatologia , Neovascularização Patológica/prevenção & controle , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacosRESUMO
Ras proteins signal to a number of distinct pathways by interacting with diverse effectors. Studies of ras/effector interactions have focused on three classes, Raf kinases, ral guanylnucleotide-exchange factors, and phosphatidylinositol-3-kinases. Here we describe ras interactions with another effector, the recently identified phospholipase C epsilon (PLCepsilon). We solved structures of PLCepsilon RA domains (RA1 and RA2) by NMR and the structure of the RA2/ras complex by X-ray crystallography. Although the similarity between ubiquitin-like folds of RA1 and RA2 proves that they are homologs, only RA2 can bind ras. Some of the features of the RA2/ras interface are unique to PLCepsilon, while the ability to make contacts with both switch I and II regions of ras is shared only with phosphatidylinositol-3-kinase. Studies of PLCepsilon regulation suggest that, in a cellular context, the RA2 domain, in a mode specific to PLCepsilon, has a role in membrane targeting with further regulatory impact on PLC activity.