sli-1 is a negative regulator of
let-23-mediated vulval induction and encodes a protein similar to the mammalian proto-oncoprotein c-Cbl1. Reduction-of-function (rf) mutations in
sli-1 suppress the vulvaless (Vul) phenotype associated with severe reduction-of-function, but not null, mutations of
let-232; LET-23 is a C. elegans homolog of the mammalian EGF receptor-tyrosine-kinase.
let-60 Ras acts downstream in the signal transduction process initiated by LET-23. Previous studies have shown that
sli-1 only weakly suppresses the slight Vul phenotype associated with the
let-60(rf) mutation,
n20212. We have furthered this study and have determined that
sli-1 does not measurably suppress the Vul phenotype associated with severe, non-null
let-60(rf) mutations. In contrast, we have determined that
sli-1(rf) does strongly suppress the Vul phenotype associated with a severe, non-null
sem-5(rf) mutation,
n1619; SEM-5 is a Grb-2-like adaptor that acts downstream of LET-23 RTK and upstream of LET-60 Ras. We conclude that SLI-1 regulates, directly or indirectly, Ras activation. Minigene constructs of the full-length
sli-1 cDNA have been made and shown to have wild-type
sli-1 function in vulval induction in germline rescue experiments. However, the human c-cbl cDNA does not substitute for wild-type
sli-1 activity. We are making
sli-1/c-cbl chimeric constructs as well as mutant constructs of
sli-1 and c-cbl driven by heatshock promoters to test for their effects in vulval induction. 1. Yoon, C. H. et al. (1995) Science 269: 1102-1105. 2. Jongeward, G. D. et al. (1995) Genetics 139: 1553-1566.