Conspiracy Theory RAS and RAF Do Not Act Alone

Several recent papers have added new proteins that conspire with RAS, RAF, and receptors to transduce signals. These new findings raise many more questions than they answer and suggest that we need to reevaluate RAS and RAF signaling and its regulation. Pasadena, California 91125 SUR-8/SOC-2 Helps RAS EGF receptor signaling in C. elegans has been most extensively analyzed in the context of vulval develop-Introduction ment, which provides a facile assay for RAS activity. In the early 1990s, genetic analysis in D. melanogaster Mutants of RAF, MEK, MAP kinase, and KSR-1 suppress and C. elegans helped define a signaling pathway from the effects of activated RAS in C. elegans. Recently, a cell surface receptors to the nucleus. Cell surface recep-new protein, SUR-8 (Suppressor of RAS), was identified tors with intrinsic tyrosine kinase activity (receptor tyro-in this way (Sieburth et al., 1998). This protein was also sine kinases or RTKs) respond to peptide ligands, identified as acting downstream of the C. elegans FGFR, growth factors, and inductive signals in development. which when constitutively active leads to a phenotype Activation of RTKs often leads to activation of RAS, called Clear (hence soc-2, Suppressor of clear; Selfors which in its GTP-bound state activates effectors, the et al., 1998). Mutants of SEM-5 or SOC-2 disrupt sig-proteins that exert its biological effect. The identification naling by activated FGFR. Because SUR-8/SOC-2 is of SOS (Son of sevenless) as a guanine nucleotide ex-necessary for the action of activated FGFR and of RAS, change factor for RAS, and the adaptor protein GRB2 SUR-8/SOC-2 is likely to be a positive regulator in RAS (in mammals)/SEM-5 (in C. elegans)/DRK (in Drosophila), signaling. coupled with the finding that these two proteins act SUR-8/SOC-2 and a human homolog have 18 leucine-downstream of RTKs and upstream of RAS, allowed rich repeats (LRRs), a relatively common protein–protein the biochemical linking of RTKs to RAS activation. The interaction motif (Kobe and Deisenhofer, 1994) and one adaptor GRB2 binds to proteins phosphorylated on tyro-that is found in adenylyl cyclase, an effector for S. cere-sine by RTKs and thereby recruits SOS to the membrane, visiae RAS. Indeed, SUR-8/SOC-2 binds to RAS but not allowing it to activate RAS. Similarly, the finding that the RAF, MEK, MAPK, or KSR-1 by yeast two-hybrid assays. serine/threonine protein kinase RAF acts downstream In vitro, SUR-8/SOC-2 binds the effector domain of RAS. of RAS led to its identification as a bona fide effector …