Figure 6. Multiple modes of crosstalk between the RAS/MAPK and insulin pathways during vulval development.

Activation of LET-60 RAS in the VPCs causes phosphorylated MPK-1 to enter the nucleus where it phosphorylates transcription factors such as LIN-1 ETS, which represses 1° fate-specific gene expression. The insulin signaling pathway interacts with the RAS/MAPK pathway at several levels. Firstly, DAF-2 InsR activation enhances RAS/MAPK signaling by stimulating the PI3K AGE-1, which positively regulates RAS/MAPK signaling via increased PIP₃ production. In addition, DAF-2 signaling activates the RAS/MAPK signaling independently of AGE-1, possibly by recruiting SEM-5 to the plasma membrane. DAF-18 PTEN inhibits RAS/MAPK signaling in two distinct manners; by dephosphorylating PIP₃ and by negatively regulating MAPK activation.