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.
PubMed ID: 18697906
Article link: Development.
Grant support: GM60501 NIGMS NIH HHS , Cancer Research UK, R01 GM060501-07 NIGMS NIH HHS , R01 GM060501-08 NIGMS NIH HHS , R01 GM060501 NIGMS NIH HHS
Genes referenced: gsc nodal odc1 ppp2r2a ppp2r2d ppp2r4 smad2 t tgfb1
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|Fig. 2. Manipulating the expression of Bα and Bδ in Xenopus embryos has opposing effects on Activin/Nodal target gene expression. (A) In situ hybridisation of gastrula-stage embryos injected with either a morpholino control (MoC) or a specific morpholino against Xenopus Bα (MoBα) or Bδ (MoBδ), or with Flag-tagged mouse Bδ mRNA (Bδ) at the one-cell stage. The probes used were against gsc or Xbra. Staining was visualised with BM purple. There is increased staining for both Xbra and Gsc in Bδ morphants, and decreased staining in Bα morphants and embryos overexpressing Bδ. (B) Analysis of gene expression by q-PCR. Total RNA was isolated from stage 10.5 embryos that had been injected at the one-cell stage with either morpholino control, or morpholinos against Bα or Bδ. Expression levels are normalised to ornithine decarboxylase (ODC).|