Ras-Dependent Cell Fate Decisions Are Reinforced by the RAP-1 Small GTPase in Caenorhabditis  elegans. Issue 4 (26th September 2018)

• Record Type: Journal Article
• Authors: Rasmussen, Neal R; Dickinson, Daniel J; Reiner, David J
• Is Part Of: Genetics. Volume 210:Issue 4(2018)
• Page Start: 1339
• Page End: 1354
• Publication Date: 2018-09-26
• Subjects: Ras -- Rap1 -- Raf -- PDZ-GEF -- CRISPR; Genetics -- Periodicals; 576.5
• DOI: 10.1534/genetics.118.301601
• Languages: English
• ISSNs: 0016-6731

Abstract

Abstract: Investigation into the signaling relationship between closely related small GTPases Ras and Rap1 has a complicated past. Rasmussen, Dickinson, and Reiner use Caenorhabditis elegans to investigate the role of RAP-1 in LET-60/ Ras-dependent developmental events... 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.