Regulation of Ras proteins.

Ras GTPase regulation has been extensively studied in other systems (Malumbres and Barbacid, 2002). Ras-GDP is inactive, whereas Ras-GTP is active and can bind to effectors such as Raf. Guanine nucleotide exchange factors (GEFs) such as SOS-1 positively regulate Ras by promoting GDP dissociation. GTPase activating proteins (GAPs) negatively regulate Ras by stimulating Ras’ intrinsic GTP hydrolyzing activity. Gain-of-function (gf) mutations lock Ras in the active, GTP-bound state; the let-60(gf) allele n1046 (G13E) has been widely used for genetic analyses (Beitel et al., 1990; Han and Sternberg, 1990). Dominant-negative (dn) mutations lock Ras in the inactive, GDP-bound state, causing it to bind stably to and titrate out GEFs; a variety of let-60(dn) mutations have been described (Han and Sternberg, 1991).