Protein intracellular activation

Fatty acid transport proteins (FATPs) are an evolutionary conserved family of integral membrane proteins found at the plasma membrane and on internal membranes. FATPs facilitate the unidirectional uptake and/ or intracellular activation of unesterified long-chain and very long-chain fatty acids (LCFAs) into a variety of lipid-metabolizing cells and tissues. 

Besides cytoplasmic protein kinases, membrane receptors can exert protein kinase activity. These so-called receptor tyrosine kinases (RTK) contain a ligandbinding extracellular domain, a transmembrane motif, and an intracellular catalytic domain with specificity for tyrosine residues. Upon ligand binding and subsequent receptor oligomerization, the tyrosine residues of the intracellular domain become phosphory-lated by the intrinsic tyrosine kinase activity of the receptor [3, 4]. The phosphotyrosine residues ftmction as docking sites for other proteins that will transmit the signal received by the RTK. 

The exact molecular mechanisms by which TNF-induced signal transduction are mediated remain to be characterized in detail. Oligomerization of the receptors is often followed by their phosphorylation, most likely by accessory kinases that associate with the intracellular domain of the receptor (neither receptor type displays intrinsic protein kinase activity). The existence of several phosphoproteins capable of associating with (the intracellular domain of) TNF-R55 and TNF-R75 have also been established. Following clustering of the TNF receptors, these... 

It is not clear whether V(V) or V(IV) (or both) is the active insulin-mimetic redox state of vanadium. In the body, endogenous reducing agents such as glutathione and ascorbic acid may inhibit the oxidation of V(IV). The mechanism of action of insulin mimetics is unclear. Insulin receptors are membrane-spanning tyrosine-specific protein kinases activated by insulin on the extracellular side to catalyze intracellular protein tyrosine phosphorylation. Vanadates can act as phosphate analogs, and there is evidence for potent inhibition of phosphotyrosine phosphatases (526). Peroxovanadate complexes, for example, can induce autophosphorylation at tyrosine residues and inhibit the insulin-receptor-associated phosphotyrosine phosphatase, and these in turn activate insulin-receptor kinase. 

The integrins comprise a family of cell-surface proteins that are involved in adhesion, a process vital for many processes, such as anchorage, migration, growth and differentiation. Cells may adhere to other cells (cell-cell adhesion) or may interact with soluble molecules that constitute the extracellular matrix (cell-extracellular matrix). The integrins are linked to elements of the cytoskeleton, and so they provide a bridge between the external cellular environment and intracellular activation processes. 

An, S., Bleu, T. and Zheng, Y., 1999, Transduction of intracellular calcium signals through G protein- mediated activation ofphosphohpase C by recombinant sphingosine 1- phosphate receptors. Mol. Pharmacol. 55 787-794. 

The functional proteins in the cell have to be protected in order to prevent premature degradation. Some of the intracellularly active proteolytic enzymes are therefore enclosed in lysosomes (see p. 234). The proteinases that act there are also known as cathepsins. Another carefully regulated system for protein degradation is located in the cytoplasm. This consists of large protein complexes (mass 2 10 Da), the proteasomes. Proteasomes contain a barrel-shaped core consisting of 28 subunits that has a sedimentation coef cient (see p. 200) of 20 S. Proteolytic activity (shown here by the scissors) is localized in the interior of the 20-S core and is therefore protected. The openings in the barrel are sealed by 19-S particles with a complex structure that control access to the core. 

The TGF- Ss exert their biological actions by binding to specific receptors, of which there are three types (I, II and III). All are transmembrane glycoproteins. All three TGF-)Ss bind to all three receptor types, although they bind with higher affinity to types I and II receptors (53 kDa and 65 kDa, respectively). The intracellular domains of the type I and II receptors display endogenous serine/threonine protein kinase activity. 

The intracellular signaltransduction of ofi-adrenoceptors is effectuated by a G-protein-dependent activation of the phospholipase C. This enzyme cleaves phosphatidylinositol, a phospholipid present in cell membranes, into inositol-1,4-5-triphosphate (IP3) and diacylglycerol (DAG). IP3 is a strong inductor of intracellular calcium release which leads to an increase of smooth muscle tone or the liberation of hormones stored in vesicles. Noradrenaline which is released by exocytosis, spreads by diffusion only. Only a small fraction of the total amount of the transmitter released will actually reach the postsynaptic membrane and bind to its specific receptors. Another fraction escapes the synapic cleft by diffusion and is finally enzymatically degraded in the interstitial fluid. Another fraction is taken up postsynaptically and metabolized enzymatically by the target cells (uptake 2). By far most of the transmitter (90%) is actively taken up by the releasing neuron itself (uptake 1 or neuronal re-uptake). In the... 

The immediate effect of increasing intracellular cAMP levels is an increase in contractility. This has been observed repeatedly in acutely ill patients in the intensive care unit with the intravenous infusion of either (3-adrenergic agonists (e.g., dobutamine) or the phosphodiesterase inhibitors milrinone (Corotrope) and am-rinone (Inocor). Binding of dobutamine to cardiac myocyte adrenoceptors results in G-protein coupling, activation of adenylyl cyclase, and the conversion of ATP to cAMP. 

Intracellular signal conduction takes place predominantly by two pathways starting from activated transmembrane receptors. In one pathway, activation of transmem -brane receptors initiates formation of diffusible messenger substances that bind effector proteins and activate these for further signal transduction. In this signaling pathway, signals may be carried as far as the cell nucleus and temporally and spatially variable reactions may be triggered. 

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