Intracellular signal transducers

The protein Ras, an important intracellular signal transducer, is crucially involved in the development of tumor growth. The farnesylation of Ras, catalyzed by the enzyme Ras-farnesyl-transferase, is essential to its proper functioning in the normal and in the transformed state. Therefore, the inhibition of Ras lipidation has become a promising target for the development of new classes of anti-tumor agents. This review focuses on the different classes of Ras-farnesyl-transferase inhibitors and compares their biological properties and modes of action in vitro as well as in vivo. 

As we mentioned earlier, Ca2+ is a component of a number of intracellular signal-transducing pathways, including the phosphoinositide cascade (Figure 11.8). We also mentioned that... 

In addition to phosphorylating itself, the insulin receptor catalyzes the tyrosine phosphorylation of a number of specific intracellular proteins (see Figure 25-14). These include the four members of the family of insulin-receptor substrate (IRS) proteins (termed IRS-1, IRS-2, IRS-3, and IRS-4), She, and Gab-1. The phosphorylated tyrosines on these target proteins act as docking sites for selected intracellular signal transducer proteins. Most of these transducer proteins contain one or more Sre homology 2 (SH2) domains. The SH2 domain is a sequence of approximately 100 amino acids... 

PI3Ks are a large family of intracellular signal transducers that have attracted much attention over the past 10 years. 

The plasma membranes of many types of eukaryotic cells also contain receptor proteins that bind specific signaling molecules (e.g., hormones, growth factors, neurotransmlt-ters), leading to various cellular responses. These proteins, which are critical for cell development and functioning, are described in several later chapters. Finally, peripheral cytosolic proteins that are recruited to the membrane surface function as enzymes. Intracellular signal transducers, and structural proteins for stabilizing the membrane. 

To identify Intracellular signal-transducing proteins in the Sev RTK pathway, investigators produced mutant flies expressing a temperature-sensitive Sev protein. When these flies were maintained at a permissive temperature, all their ommatidia contained R7 cells when they were maintained at a nonpermissive temperature, no R7 cells developed. At a par-... 

Cathine is a known inhibitor of monoamine oxidase and a central stimulant as an indirect sympathomimetic. It is found in anorectic products. Cathine is reported to be a stimulant alkaloid in the natural reproduction ability of sperm and can be used clinically in reducing or enhancing natural fertil-ity 1,105 findings suggest that cathine reduces posttranslational modification of intracellular signal transducers in killer cells and monocytes and results in signaling profiles with B-lymphocytes and natural killer cells. Norephedrine has an identical or similar stimulation activity as cathine. 

It is worth mentioning that membrane-bound forms of GC, which can be considered signal transducing enzymes , are structurally homologous to other signal transducing enzymes, such as certain protein tyrosine kinases and phosphatases, which also possess receptor moieties in their extracellular (amino terminus) domain and enzyme catalytic activity in their intracellular domain (see Ch. 24). Activation of many of these receptors occurs upon ligand-induced dimerization of the receptors, and a similar... 

The neurotrophins interact with two distinct cell surface receptor species [5,6,9] (Fig. 27-2). The neurotrophins bind to the Trk family of receptors, which serve as the principal signal transducer for this class of growth factors. The Trk receptors comprise a small, highly related family of molecules that possess an extracellular ligand binding domain that selectively interacts with the individual neurotrophin species. Trk A specifically binds NGF, TrkB interacts with BDNF and NT4/5, and TrkC preferentially binds NT3. Importantly, the Trk receptors have an intracellular tyrosine kinase domain that is activated upon neurotrophin binding. The kinase domains of the Trk family members are highly conserved and the Trks differ mainly in the structure of their extracellular domains. Trk receptor expression is limited to neurons and the... 

These signal transducers have a large extracellular domain with its ligandbinding site, a single transmembrane domain and an intracellular domain with intrinsic tyrosine kinase activity. 

Cytokine receptors, like receptor tyrosine kinases, have extracellular and intracellular domains and form dimers. However, after activation by an appropriate ligand, separate mobile protein tyrosine kinase molecules (JAK) are activated, resulting in phosphorylation of signal transducers and activation of transcription (STAT) molecules. STAT dimers then travel to the nucleus, where they regulate transcription. 

A cell is enclosed by a lipid bilayer known as the plasma membrane. In Vignette 1.2 in Chapter 1 we discussed an example of a membrane, a complex structure with a mosaic of embedded or adsorbed moieties such as proteins. It is these membranes that protect the intracellular contents from the exterior environment of the cells and regulate the transport of materials into and out of the cells. They can also act as signal transducers and control the electrical excitation in the nervous system by altering the (membrane) permeability to particular ions in response to stimuli. Such electrical activities can propagate over long distances and represent one of the most spectacular of the membrane functions. 

As noted earlier, signal-transducing systems undergo desensitization when the signal persists. Desensitization of the /3-adrenergic receptor is mediated by a protein kinase that phosphorylates the receptor on the intracellular domain that normally interacts with Gs (Fig. 12-17). When the receptor is occupied by epinephrine,... 

The leptin signal is transduced by a mechanism also used by receptors for interferon and growth factors, the JAIC-STAT system (Fig. 23-34 see Fig. 12-9). The leptin receptor, which has a single transmembrane segment, dimerizes when leptin binds to the extracellular domain of two monomers. Both monomers are phos-phorylated on a Tyr residue of the intracellular domain by a Janus kinase (JAK). The -Tyr residues become docking sites for three proteins that are signal transducers and activators of transcription (STATs 3, 5, and 6, sometimes called fat-STATS). The docked STATs are then phosphorylated on Tyr residues by the... 

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