Ras-signaling pathway

Gulbins, E, Bissoimette, R., Mahboubi, A., Martin, S., Nishioka, W., Bmnner, T., Baier, G., Baier-Bitterbch, G., Byrd, C., Lang, E, Kolesnick, R, Altman, A., Green, D., 1995, FAS-induced apoptosis is mediated via a ceramide-initiated RAS signaling pathway. Immunity 2 341-351... 

The Sos recruitment yeast two-hybrid system was developed by Aronheim and colleagues (1997). It is now known as the CytoTrap yeast two-hybrid system and marketed by Stratagene (La Jolla, California, USA). The CytoTrap system differs from both the GAL4 and the LexA systems in that it is not dependent on transcription factor activation in the nucleus for the detection of protein-protein association. Instead, protein interactions are detected in the cytoplasm and involve the reconstitution of the Sos/Ras signaling pathway in conjunction with the temperature-sensitive yeast strain, cdc25H. 

Rellahan, B. L., L. J. Graham, B. Stoica, K. E. DeBell, and E. Bonvini. Cbl-mediated regulation ofT cell receptor-induced AP1 activation. Implications for activation via the Ras signaling pathway. J Biol Chem. 272 30806-11.1997. 

Bourtchuladze R, Abel T, Berman N, Gordon R, Lapidus K, Kandel ER (1998) Different training procedures recruit either one or two critical periods for contextual memory consolidation, each of which requires protein synthesis and PKA. Learn Mem 5 365-374 Brambilla R, Gnesutta N, Minichiello L, White G, Roylance AJ, Herron GE, Ramsey M, Wolfer DP, Cestari V, Rossi-Arnaud C, Grant SG, Chapman PE, Lipp HP, Sturani E, Klein R (1997) A role for the Ras signalling pathway in synaptic transmission and long-term memory. Nature 390 281-286... 

The P13-kinase has also been identified as a part of the Ras signaling pathway (see Chapter 9). Signals originating from transmembrane receptors can be transmitted from the Ras protein to P13-kinase. In this case, the P13-kinase acts as the effector molecule of the Ras protein. 

It is not surprising that residues corresponding to switch I and switch II, which define the conformational differences between the inactive GDP form and the active GTP state of Ras, are involved in recognition of the Ras effectors, the immediate downstream components in the Ras signaling pathway (see 9.6 and 9.7). Residues 32-40 comprise the core Ras effector domain, which is essential for all effector interactions. 

Fig. 9.12. Overview of the Ras signaling pathway. Signals from at least three major signaling pathways meet at the Ras protein. Activation of the Ras protein may be initiated by receptor tyrosine kinases, by G-protein-coupled receptors and by receptors with associated tyrosine kinases. The nature of the communication between the Ras protein and receptors with associated tyrosine kinase or G-protein-coupled receptors is mostly unknown. From the activated Ras protein, the signal is passed to various effector molecules including members of the MEK kinases, PI3-kinase, pl20 GAP and Ral-GEFs. The best understood is the effector function of Raf kinase, which passes a signal to the transcription level via the MAP kinase pathway.

Park JI, Lee MG, Cho K, Park BJ, Chae KS, Byun DS, Ryu BK, Park YK, Chi SG. 2003. Transforming growth factor-betal activates interleukin-6 expression in prostate cancer cells through the synergistic collaboration of the Smad2, p38-NF-kappaB, JNK, and Ras signaling pathways. Oncogene 22 4314-4332. 

In addition to the CTE assay, a second measure of specificity was provided by the selective growth inhibition of ras-transformed cells vs. control cell lines which should be insensitive to the effects of an FTI. For example, cell lines transformed with proteins that are not part of the Ras signaling pathway, or which are part of the Ras signaling pathway but which operate downstream from Ras, should not be affected by an FTI. This type of selectivity was demonstrated for a number of different prodrugs using H-ras transformed cells and either mos- or ra/-transformed cells. 

Downward, J. (2003). Targeting ras signalling pathways in cancer therapy. Nat Rev Cancer 3 11-22. 

After being phosphorylated, IRS provokes the activation of two separate pathways within the cell. From the IRS branching point come two signaling pathways, in the manner of two branches. These two branches are the PI 3-kinase signaling pathway and the RAS signaling pathway (Lawrence and Roach, 1997 Taha et ah, 1995) (Figure 4.13B). The branching point is represented by... 

In the late 1980s, the cloning ofthe nuclear RA receptor a (RARa) (6,7) opened an avenue for the dissection of the RA signaling pathways. Subsequently, the detection of endogenous RA in animals substantiated the notion that RA could be the physiologically active component of vitamin A (4). This was further supported... 

Downward J. 2002. Targeting RAS signaling pathways in cancer therapy. Nat. Rev. Cancer 3 11-21. 

The colocalization of signaling proteins is essential for the signaling at the cell membrane. The transduction of signals by transmembrane receptors into the interior of the cell occurrs in multiprotein complexes assembled specifically at the inner face of the cell membrane. A large part of the Ras signaling pathway (see Chapter 9) is intimately linked to the cytoplasmic side of the membrane. If membrane association of the components of the Ras signaling pathway is prevented, signal transduction is shut down. 

In this section, we first examine the components of the kinase cascade downstream from Ras in RTK-Ras signaling pathways in mammalian cells. Then we discuss the linkage of other signaling pathways to similar kinase cascades, and we examine recent studies indicating that both yeasts and cells of higher eukaryotes contain multiple MAP kinase pathways. 

---