Ras signaling

N-ras, H-ras, K-ras Signal transduction pathway Inhibition of cell proliferation and colony formation change in morphology, enhanced melanin synthesis decrease of in vivo tumorigenicity... 

Sorafenib is a multitargeted cancer therapy that inhibits VEGFR, PDGFR, KIT, fetal liver tyrosine kinase 3 (FLT-3), and the serine/threonine kinase RAF. RAF kinase is a key downstream effector of Ras in the MAPK/Ras signal-transduction pathway that has been linked to various cancers. Sorafenib is both a tyrosine kinase inhibitor and serine/threonine signal-transduction inhibitor. Sorafenib has been approved in renal cancer. 

This section explains how genetic studies with Drosophila and Caenorhabditis elegans have contributed to the discovery of the Ras signal-transduction pathway operative in mammalian cells. 

Raabe, T. and Rapp, U. R. Ras signaling PP2A puts Ksr and Raf in the right place. Curr. Biol. 13 R635-R637, 2003. 

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]. 

The Ras signal transduction cascade is of extreme physiological importance. It is central to the regulation of cell growth and differentiation, and false regulation of this signal pathway can be one of the critical steps leading to cell transformation.151 A... 

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. 

Ras Signal transduction factors Monomeric G-protein with very low GTPase activity, which maintains the protein in the active state. 

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. 

To function, Ras must be attached to the plasma membrane. Translocation from the cytoplasm to membrane requires a series of posttranslational modifications that begin with farnesylation of the cysteine residue, the fourth amino acid residue from the C terminus of the protein, by famesyl protein transferase (FPTase) (64). Attachment of the hydrophobic 15-carbon lipid farnesyl group allows Ras molecule insertion into the plasma membrane and is crucial for Ras signaling activity and transformation properties. As farnesylation is required for oncogenic Ras function, FPTase inhibitors (FTIs) are obvious candidate antineoplastic agents. Several drugs that inhibit Ras farnesylation are at various stages of clinical development (65). 

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. 

The adaptor protein Grb2 of Ras signal transduction (see 8.5 and Chapter 9)... 

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. 

The Sos-Grb2 complex can participate in Ras signal transduction by two pathways. In one pathway, the SH2 domain of Grb2 binds to the phosphotyrosine of the activated receptor, whereby the Grb2-mSos complex, which is predominantly localized in the cytoplasm, is brought to the receptor and thus to the cell membrane (Fig. 9.9). 

---