Insulated Switches: Dual-Function Protein RalGEF Promotes Developmental Fidelity.

The vulva is an excellent model for the study of developmental biology and cell-cell signaling. The developmental induction of vulval precursor cells (VPCs) to assume the 3°-3°-2°-1°-2°-3° patterning of cell fates occurs with 99.8% accuracy. During vulval development, an EGF signal from the anchor cell initiates the activation of Ras > Raf > MEK > ERK signaling cascade to induce the 1° cell. The presumptive 1° cell signals its two neighboring cells via Notch to develop 2° cells. In addition, Ras switches effectors to RalGEF > Ral to promote 2° fate. Shin et al. (2019) showed that RalGEF is a dual-function protein in VPCs fate patterning. RalGEF functions as a scaffold for PDK > Akt modulatory signaling to promote 1° fate in addition to propagating the Ras modulatory signal through Ral to promote 2° fate. The deletion of RalGEF increases the frequency of VPC patterning errors 15-fold compared to the wild-type control. We speculate that RalGEF represents an "insulated switch", whereby the promotion of one signaling activity curtails the promotion of the opposing activity. This property might increase the impact of the switch on fidelity more than two separately encoded proteins could. Understanding how developmental fidelity is controlled will help us to better understand the origins of cancer and birth defects, which occur in part due to the misspecification of cell fates.