Ras activation

Joly observed elevated "Ra activities in deep-sea sediments that he attributed to water column scavenging and removal processes. This hypothesis was later challenged with the hrst seawater °Th measurements (parent of "Ra), and these new results conhrmed that radium was instead actively migrating across the marine sediment-water interface. This seabed source stimulated much activity to use radium as a tracer for ocean circulation. Unfortunately, the utility of Ra as a deep ocean circulation tracer never came to full fruition as biological cycling has been repeatedly shown to have a strong and unpredictable effect on the vertical distribution of this isotope. 

The extended ternary complex model [23] was conceived after it was clear that receptors could spontaneously activate G-proteins in the absence of agonist. It is an amalgam of the ternary complex model [12] and two-state theory that allows proteins to spontaneously exist in two conformations, each having different properties with respect to other proteins and to ligands. Thus, two receptor species are described [Ra] (active state receptor able to activate G-proteins) and [RJ (inactive state receptors). These coexist according to an allosteric constant (L = [Ra]/[Ri]) ... 

Ras activates a number of pathways among them is the mitogen-activated protein (MAP) kinases, which transmit signals downstream to other protein kinases and gene regulatory proteins... 

As a noble gas, Rn in groundwater does not react with host aquifer surfaces and is present as uncharged single atoms. The radionuclide Rn typically has the highest activities in groundwater (Fig. 1). Krishnaswami et al. (1982) argued that Rn and all of the other isotopes produced by a decay are supplied at similar rates by recoil, so that the differences in concentrations are related to the more reactive nature of the other nuclides. Therefore, the concentration of Rn could be used to calculate the recoil rate for all U-series nuclides produced by a recoil. The only output of Rn is by decay, and with a 3.8 day half-life it is expected to readily reach steady state concentrations at each location. Each measured activity (i.e., the decay or removal rate) can therefore be equated with the input rate. In this case, the fraction released, or emanation efficiency, can be calculated from the bulk rock Ra activity per unit mass ... 

Plater AJ, Ivanovich M, Dugdale RE (1995) Ra contents and Ra/ Ra activity ratios of the Fenland rivers and the Wash, eastern England spatial and seasonal trends. Chem Geol 119 275-292 Pliler R, Adams JAS (1962) The distribution of thorium and uranium in a Pennsylvanian weathering profile. Geochim Cosmochim Acta 26 1137-1146... 

This equation is particularly useful to derive apparent estuarine water mass ages (Fig. 6) because the term /em is removed. Using ( Ra/ " Ra) isotope ratios in this manner is based on the assumption that the initial ( Ra/ " Ra) activity ratio must remain constant. This conclusion is reasonable as the long-lived parent isotopes ( Pa and Th) have relatively constant activity ratios in sediments, and the intermediate Th isotopes ( Th and Th) are scavenged efficiently in the near-shore water column. The utility of Ra as... 

Atchafalaya and Mississippi Rivers. Florida Bay waters, which overlie U-rich sediments, contain much higher ( Ra/ " Ra) activity ratios than other estuaries. The increased ( Ra/ " Ra) values observed at high salinities in the Mississippi/Atchafalaya systems indicate preferential decay of the shorter-lived ""Ra over Ra during estuarine mixing. 

FIGURE 2 0-5 Activation of PLC-e by heterotrimeric (Gal2/i3, GI(Vy, GJ and small G protein (Ras, Rho and Rap) signaling pathways (see text for details). (Modified with permission from reference [11].) Note that Ras, activated via the mitogen-activated protein kinase (MAPK) pathway, may also activate PLCe. For details of the MAPK pathways and abbreviations, see Chapter 24. 

Multiple interactions are also being demonstrated between the traditional second-messenger pathways and the MAPK cascades. Free (3y G protein subunits, generated upon activation of receptors coupled to the G family, lead to activation of the ERK pathway. The mechanism by which this occurs, which may involve an interaction between the subunits and Ras or Raf, is a subject of intensive research (see Ch. 19). In addition, increases in cellular Ca2+ concentrations lead to stimulation of the ERK pathway, apparently via phosphorylation by CaMKs of proteins, for example She and Grb, that link growth factor receptor tyrosine kinases to Ras. Activation of the... 

Ral has attracted much interest in recent years, not least because it was demonstrated to mediate part of Ras function as described above. In contrast to Rap, which rather inhibits Ras signaling, Ral is part of one of the essential Ras-activated pathways. Moreover, it has proved to be acting in parallel with the Raf pathway in cell transformation induced by oncogenic Ras [37, 77]. The case of Ral demonstrates the complexity - and the incomplete knowledge and understanding - of signal transduction. Ral can also be activated by Rap mediated by Rif [103] and, alternatively, by binding of a calcium/calmodulin complex to the Ral C-terminus which obviously does not affect the nucleotide state of Ral [111]. 

There are several possible explanations to account for this apparent lack of toxicity. Some geranylgeranylated Ras-related proteins might compensate for the loss of Ras function (see, e.g., [46]). Alternatively inhibition of farnesyl transferase may reduce Ras activity below the level required for transformation, yet allow sufficient Ras activity for maintaining normal cell viability [47]. Alternatively, a different signaling pathway may be activated when Ras is not anchored to the plasma membrane. 

Figure 6.4. Mode of action of low-molecular-weight G-proteins. The raslike proteins normally bind GDP, but this may be exchanged for GTP via a process that may be assisted by guanine nucleotide exchange protein (GNEP). The GTP-bound ras protein may then interact with and activate its target protein (X). The activity of GTPase activating protein (GAP) may then assist to hydrolyse GTP to GDP, to inhibit ras activity.

---