The Protein Phosphatase 4 complex promotes the Notch pathway andwinglesstranscription

Abstract

The Wnt/Wingless (Wg) pathway controls cell fate specification, tissue differentiation and organ development across organisms. Using an in vivo RNAi screen to identify novel kinase and phosphatase regulators of the Wg pathway, we identified subunits of the serine threonine phosphatase Protein Phosphatase 4 (PP4). Knockdown of the catalytic and regulatory subunits of PP4 cause reductions in the Wg pathway targets Senseless and Distal-less. We find that PP4 regulates the Wg pathway by controlling Notch-driven wg transcription. Genetic interaction experiments identified that PP4 likely promotes Notch signaling within the nucleus of the Notch-receiving cell. Although the PP4 complex is implicated in various cellular processes, its role in the regulation of Wg and Notch pathways was previously uncharacterized. Our study identifies a novel role of PP4 in regulating Notch pathway, resulting in aberrations in Notch-mediated transcriptional regulation of the Wingless ligand. Furthermore, we show that PP4 regulates proliferation independent of its interaction with Notch.

The ATPase TER94 regulates Notch signaling duringDrosophilawing development

“…5B). By examining Notch target gene expression, we could determine in which cells TER94 is working to affect the Notch pathway (Hall et al, 2017). C5>TER94 AA appeared to have no effect on Cut expression (Fig.…”

The PP2A/4/6 subfamily of phosphoprotein phosphatases regulates DAF-16 and confers resistance to environmental stress in postreproductive adult C. elegans

“…We then functionally characterized smk-1 by assessing its contribution to the ability of animals to resist acute environmental insults including bacterial infection with Pseudomonas aeruginosa (PA14), exposure to elevated temperature, and irradiation with ultraviolet (UV) light. In each stress assay, the phenotype resulting from smk-1 knockdown was compared to the effect of knocking down daf- 16.…”

“…RNAi targeting PP4 subunit orthologs pph-4.2 and ppfr-2 had no effect on the survival of infected Day 6 adult daf-16(mgDf47) mutants (Fig 7A and 7B), suggesting that they confer resistance to bacterial infection through the same pathway as daf- 16. Surprisingly, knockdown of pph-4.1, the paralog of pph-4.2 encoding the catalytic subunit of PP4, suppressed the enhanced susceptibility phenotype of Day 6 daf-16 (mgDf47) mutants as did knockdown of let-92, the ortholog of the PP2A catalytic subunit, although to a lesser extent.…”

“…Phosphoprotein phosphatases (PPPs) comprise a large class of evolutionarily conserved enzymes, that antagonize kinases by removing phosphate groups from a broad repertoire of substrates. In evolutionarily diverse species, the PP2A/4/6 subfamily regulates a wide array of processes, including cell cycle progression, meiosis, cellular differentiation, and the activity of multiple signaling pathways including the IIS pathway [15][16][17][18][19][20][21][22][23][24][25]. In C. elegans PP4 is not the only member of the PP2A/4/6 family with a connection to the insulin signaling pathway.…”

A PP4 foszfatáz kölcsönható partnereinek azonosítása és szubsztrátum-felismerő mechanizmusának feltárása

“…A PP4c magasabbrendű eukariótákban a legtöbb szövettípusban kifejeződik, legmagasabb szinten a herékben, vesében, idegsejtekben, májban és tüdőben [55]. Számos organizmusban a kifejeződési mintázata változik a fejlődési során, tehát fontos szerepet tölt be az ontogenezis szabályozásában is [55,60,68,69].…”