Two highly related regulatory subunits of PP2A exert opposite effects on TGF-beta/Activin/Nodal signalling.
We identify Balpha (PPP2R2A) and Bdelta (PPP2R2D), two highly related members of the B family of regulatory subunits of the protein phosphatase PP2A, as important modulators of TGF-beta/Activin/Nodal signalling that affect the pathway in opposite ways. Knockdown of Balpha in Xenopus embryos or mammalian tissue culture cells suppresses TGF-beta/Activin/Nodal-dependent responses, whereas knockdown of Bdelta enhances these responses. Moreover, in Drosophila, overexpression of Smad2 rescues a severe wing phenotype caused by overexpression of the single Drosophila PP2A B subunit Twins. We show that, in vertebrates, Balpha enhances TGF-beta/Activin/Nodal signalling by stabilising the basal levels of type I receptor, whereas Bdelta negatively modulates these pathways by restricting receptor activity. Thus, these highly related members of the same subfamily of PP2A regulatory subunits differentially regulate TGF-beta/Activin/Nodal signalling to elicit opposing biological outcomes.
Batut
Julie
J
Laboratory of Developmental Signalling, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Schmierer
Bernhard
B
Cao
Jing
J
Raftery
Laurel A
LA
Hill
Caroline S
CS
Howell
Michael
M
D029404:Activin Receptors / Q000378:metabolism; D030201:Activin Receptors, Type I; D028341:Activins / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000201:enzymology; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D055457:Nodal Protein; D010641:Phenotype; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014921:Wings, Animal / Q000166:cytology; D014981:Xenopus / Q000196:embryology*; D029867:Xenopus Proteins / Q000378:metabolism
D029721:Drosophila Proteins; C526007:NODAL protein, human; D055457:Nodal Protein; C526008:Nodal protein, mouse; C512974:PPP2R2A protein, human; C525687:PPP2R2D protein, human; D021122:Protein Subunits; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; D028341:Activins; D017346:Protein Serine-Threonine Kinases; D029404:Activin Receptors; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C481805:acvr1b protein, Xenopus; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; C079898:tws protein, Drosophila