Insulated Switches: Dual-Function Protein RalGEFRGL-1 Promotes Developmental Fidelity.

Tam Duong,David J Reiner,Neal R Rasmussen

doi:10.3390/ijms21207610

Abstract

The C. elegans 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 C. elegans vulval development, an EGF signal from the anchor cell initiates the activation of RasLET-60 > RafLIN-45 > MEKMEK-2 > ERKMPK-1 signaling cascade to induce the 1° cell. The presumptive 1° cell signals its two neighboring cells via NotchLIN-12 to develop 2° cells. In addition, RasLET-60 switches effectors to RalGEFRGL-1 > RalRAL-1 to promote 2° fate. Shin et al. (2019) showed that RalGEFRGL-1 is a dual-function protein in VPCs fate patterning. RalGEFRGL-1 functions as a scaffold for PDKPDK-1 > AktAKT-1/2 modulatory signaling to promote 1° fate in addition to propagating the RasLET-60 modulatory signal through RalRAL-1 to promote 2° fate. The deletion of RalGEFRGL-1 increases the frequency of VPC patterning errors 15-fold compared to the wild-type control. We speculate that RalGEFRGL-1 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.

Highlights

The C. elegans vulva is an excellent model in which to study cell–cell signaling
We found that during the patterning of vulval precursor cells (VPCs) fates, RasLET-60 switches effectors, from RasLET-60 > RafLIN-45 promoting 1◦ fate to RasLET-60 > RalGEFRGL-1 > RalRAL-1 promoting 2◦ fate [17]
These results indicate that RalGEFRGL-1 promotes 2◦ fate via the canonical GEF-dependent activation of RalRAL-1

Summary

Introduction

The C. elegans vulva is an excellent model in which to study cell–cell signaling. Six specialized equipotent epithelial cells, the vulval precursor cells (VPCs), are arranged along the ventral midline. In response to initial patterning of VPC fates by the two core signaling cascades, Ras-Raf-MAP kinase and Notch, a series of additional signals and transcriptional changes in signaling molecules occur. These changes appear to reinforce initial patterning events and/or reduce conflicting signals within cells. RalGEFRGL-1 orchestrates the two opposing modulatory signals in VPC fate patterning: Akt promotion of 1◦ fate and Ral promotion of 2◦ fate That both activities are embodied in the same signaling molecule raises thought-provoking questions about the functional significance of this concurrence. This model casts the frequently described phenomenon of “pathway cross-talk” in an interesting new light

Two Antagonistic Functions of RalGEFRGL-1

Speculative Model

Findings

Conclusions