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Genetics. 2018 Dec;210(4):1339-1354. doi: 10.1534/genetics.118.301601. Epub 2018 Sep 26.

Ras-Dependent Cell Fate Decisions Are Reinforced by the RAP-1 Small GTPase in Caenorhabditis elegans.

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Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, Texas 77030.
Department of Molecular Biosciences, University of Texas, Austin, Texas 78705.
Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, Texas 77030


The notoriety of the small GTPase Ras as the most mutated oncoprotein has led to a well-characterized signaling network largely conserved across metazoans. Yet the role of its close relative Rap1 (Ras Proximal), which shares 100% identity between their core effector binding sequences, remains unclear. A long-standing controversy in the field is whether Rap1 also functions to activate the canonical Ras effector, the S/T kinase Raf. We used the developmentally simpler Caenorhabditis elegans, which lacks the extensive paralog redundancy of vertebrates, to examine the role of RAP-1 in two distinct LET-60/Ras-dependent cell fate patterning events: induction of 1° vulval precursor cell (VPC) fate and of the excretory duct cell. Fluorescence-tagged endogenous RAP-1 is localized to plasma membranes and is expressed ubiquitously, with even expression levels across the VPCs. RAP-1 and its activating GEF PXF-1 function cell autonomously and are necessary for maximal induction of 1° VPCs. Critically, mutationally activated endogenous RAP-1 is sufficient both to induce ectopic 1°s and duplicate excretory duct cells. Like endogenous RAP-1, before induction GFP expression from the pxf-1 promoter is uniform across VPCs. However, unlike endogenous RAP-1, after induction GFP expression is increased in presumptive 1°s and decreased in presumptive 2°s. We conclude that RAP-1 is a positive regulator that promotes Ras-dependent inductive fate decisions. We hypothesize that PXF-1 activation of RAP-1 serves as a minor parallel input into the major LET-60/Ras signal through LIN-45/Raf.


CRISPR; PDZ-GEF; Raf; Rap1; Ras

[Available on 2019-12-01]
[Indexed for MEDLINE]

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