Genetic and pharmacologic dissection of Ras effector utilization in oncogenesis.
Ras proteins function as signaling nodes that are activated by diverse extracellular stimuli. Equally complex for this family of molecular switches is the multitude of downstream effectors and the pathways that they traverse to translate extracellular signals into a spectrum of cellular consequences. To better understand the individual and collective roles of these effector signaling networks, both genetic and pharmacological tools have been developed. By either stimulating or ablating specific components in a cascade downstream of Ras activation, one can gain insight into the specific signaling underlying a particular Ras phenotype, for example, malignant transformation. In this chapter, we describe the use of activating and dominant-negative mutations, both artificial and naturally occurring, of Ras and its effectors, as well as pharmacological inhibitors used to probe the effector pathways (Raf kinase, phosphoinositol 3-kinase, Tiam1, phospholipase C epsilon, and RalGEF) implicated in Ras-mediated oncogenesis.
Campbell
Paul M
PM
Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Singh
Anurag
A
Williams
Falina J
FJ
Frantz
Karen
K
Ulkü
Aylin S
AS
Kelley
Grant G
GG
Der
Channing J
CJ
D002070:Butadienes / Q000494:pharmacology; D004847:Epithelial Cells / Q000502:physiology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D011905:Genes, ras / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D009154:Mutation; D009570:Nitriles / Q000494:pharmacology; D010053:Ovary; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D054801:Phosphoinositide Phospholipase C / Q000378:metabolism; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D015398:Signal Transduction; D048490:raf Kinases / Q000378:metabolism; D020725:ral GTP-Binding Proteins / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D002070:Butadienes; D005419:Flavonoids; D020662:Guanine Nucleotide Exchange Factors; D009570:Nitriles; C113580:U 0126; D019869:Phosphatidylinositol 3-Kinases; D048490:raf Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D054801:Phosphoinositide Phospholipase C; C423320:phospholipase C epsilon; D020725:ral GTP-Binding Proteins; D018631:ras Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one