A component of the transcriptional mediator complex inhibits RAS-dependent vulval fate specification in C. elegans.

Negative regulation of receptor tyrosine kinase (RTK)/RAS signaling pathways is important for normal development and the prevention of disease in humans. We have used a genetic screen in C. elegans to identify genes that antagonize the activity of activated LET-23, a member of the EGFR family of RTKs. We identified two loss-of-function mutations in dpy-22, previously cloned as sop-1, that promote the ability of activated LET-23 to induce ectopic vulval fates. DPY-22 is a glutamine-rich protein that is most similar to human TRAP230, a component of a transcriptional mediator complex. DPY-22 has previously been shown to regulate WNT responses through inhibition of the beta-catenin-like protein BAR-1. We provide evidence that DPY-22 also inhibits RAS-dependent vulval fate specification independently of BAR-1, and probably regulates the activities of multiple transcription factors during development. Furthermore, we demonstrate that although inhibition of BAR-1-dependent gene expression has been shown to require the C-terminal glutamine-rich region, this region is dispensable for inhibition of RAS-dependent cell differentiation. Thus, the glutamine-rich region contributes to specificity of this class of mediator protein.

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