Ras pathway

Drosophila, Caenorhabditis elegans, and the Discovery of the Ras Pathway in Vertebrates... 

Elucidation of the Ras pathway in vertebrates was based on the identification of proteins having sequence homologies with those present in Drosophila and C. elegans. Expression or microinjection... 

Edgar The protein doesn t go away. The whole system is used over and over again. The Ras pathway is required in growth in an early disc and is also used later in wings for vein—intervein patterning and in eyes for photoreceptor determination. This is all post-mitotic. 

The Ras pathway is shown here. Ras is a G-protein that couples signaling from growth factors. The activated receptor is a GNRP that increases the exchange of GDP for GTP and activates the G-protein. Ras GAP inactivates the G-protein. The downstream signal for activated Ras is eventually the mitogen-activated protein kinase pathway (MAPK). 

All steps of the Ras pathway from ligand binding to receptor tyrosine kinases, down to activation of effectors like Raf kinase, occur at the plasma membrane. However, most biophysical studies on protein/protein interactions involved in this scenario have been carried out with bacterially synthesized proteins lacking... 

In C albicans, mutations that block cAMP/PKA pathway suppress or delay the apoptotic response to H2O2 and amphotericin B. By contrast, mutations that result in constitutive activation of the RAS pathway accelerate entry into the apoptotic pathway Apoptosis and quorum sensing in filamentous fungi are phenomena associated with stress responses, a recurring motif in morphogenesis and secondary metabolism. The treatment of Colletotrichum trifolii with proline, a known stress relief chemical, suppressed apoptosis associated with Ras as well as apoptosis associated with a variety of other stresses. 

Phillips AJ, Crowe JD, Ramsdale M, Ras pathway signaling accelerates programmed cell death in the pathogenic fungus Candida albicans, Proc Natl Acad Sci USA 103 726-731, 2006. 

Fig. 11. Modes of action of fluorine on osteoblastic cells, (a) Tyrosine phosphatase hypothesis in osteoblastic cells, fluoride ion directly inhibits tyrosine phosphatase. Inhibition of this enzyme enhances the tyrosine phosphorylation of signalling molecules induced by receptor tyrosine kinase, which leads to activation of the extracellular signal-regulated kinase (ERK) through the Ras pathway and enhanced cell proliferation, (b) G-protein hypothesis in osteoblast-like cells, fluoride ions form a complex with aluminum, probably fluoroaluminate, which interacts with guanosine 5 -diphosphate (GDP) to form guanosine 5 -triphosphate (GTP)-like molecule. Activation of the G, protein stimulates the tyrosine phosphorylation of signalling molecules by a yet unknown tyrosine kinase (Tyr Kin) and activation of the ERK kinase through the Ras pathway leads to enhanced cell proliferation. (Reproduced by permission of Elsevier from Ref. [175] ...

LPA binds and activates specific G-protein-coupled receptors found in many cells (review Moolenaar et al., 1997). The LPA receptor can transmit the signal to G,-, Gj-or Gi2-proteins. If Gq is involved, an InsPs and Ca signal is produced in the cell, whereas signal conduction via Gi- or Gu-proteins flows into the Ras pathway or activates the Rho proteins, respectively (see Chapter 9). 

A primary function of the SH3 domains is to form fimctional oligomeric complexes at defined subcellular sites, frequently in cooperation with other modular domains. SH3 domains are foimd in many proteins associated with the cytoskeleton or with the plasma membrane. Examples are the actin binding protein a-spectrin and myosin lb. Furthermore, SH3 interactions are involved in signal transduction in the Ras pathway (see Chapter 9). 

Activated signals may also be transmitted along the Ras pathway from G-protein-coupled receptors. In this way, stimulation of Ras-GEFs may be mediated by the Py complex (Mattingly and Macara, 1996). 

There is evidence that signals starting from G-protein-coupled receptors run into the Ras switch station (Van Biesen et al., 1995). Pv-subunits of G-proteins are under discussion as the link between G-protein-coupled signal transduction and the Ras pathway these subunits could influence the activity of Ras protein and the subsequent MAP kinase pathway by a presently unknown mechanism. 

The Ras GTP-mediated activation of P13-kinase links the Ras pathway with fimcti-ons of the Rho/Rac proteins. Members of this protein family within the Ras superfamily control formation of the cytoskeleton. The exact nature of the linkage with the Ras/PI3-kinase signal conduction to the Rac proteins is unknown. There is evidence that the product of the P13-kinase, Ptd-lns(3,4,5)P3, binds to the PH domain of the Vav protein and activates the latter. The Vav protein functions as a nucleotide exchange factor for the Rac GTPase (Han et al., 1998). The observation that activation of the Ras pathway is accompanied by reorganization of the cytoskeleton is in agreement with these findings. 

Identification of multiple input signals and several effector proteins underlines the high complexity of signal transduction via the Ras protein. The Ras pathway cannot be seen as a linear ordering of signal elements, by which information is conducted verti-... 

Surprisingly, a growth inhibiting and pro-apoptotic function has been demonstrated for oncogenic Ras mutants. In primary cell cultures, activation of the Ras pathway is linked to an increase in the concentration of the tumor suppressor proteins p53 and pl9ARF (Serrano, 1997), which both promote programmed cell death, or apoptosis (see Chapter 15). This example shows that, according to the cellular context, the Ras protein can promote both cell death and cell survival via interactions with distinct effector proteins. 

There are also links to other members of the Ras superfamily, such as the Ral protein and the Rho/Rac proteins. The latter are involved in reorganization of the actin cytoskeleton. Transformation of cells with oncogenic Ras mutants is associated with reorganization of the actin cytoskeleton and it is assumed that this effect is due to coupling of the Ras pathways with the fimction of Rho/Rac proteins. 

Fig. 11.4. Model of signal transduction via the IL-2 receptor. Binding of IL-2 to the IL-2 receptor initiates activation of the Janus kinases Jakl and Jak3. These phosphorylate tyrosine residues in the P-chain of the IL-2 receptor and in the transcription factor StatS. SH2 domains or PTB domains of adaptor proteins can bind to the Tyr phosphate residues of the P-chain and, as shown in the figure for the Shc/Grb2/Sos complex, can transmit a signal in the direction of the Ras pathway. The phosphorylated transcription factor StatS is translocated into the nucleus and activates the transcription of corresponding gene sections. Another signaling pathway starting from the activated IL-2 receptor involves the Lck and Syk tyrosine kinases (see Chapter 8). The pathway leads to induction of genes for transcription factors such as c-Myc and c-Fos.

Lu, Y., Sakamuri, S., Chen, Q.-Z., et al. (2004) Solution phase parallel synthesis and evaluation of MAPK inhibitory activities of close structural analogues of a Ras pathway modulator. Bioorg. Med. Chem. Lett. 14, 3957-3962. 

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