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Two highly related regulatory subunits of PP2A exert opposite effects on TGF-β/Activin/Nodal signalling
Laurel A. Raftery2,
Caroline S. Hill1,, and
1 Laboratory of Developmental Signalling, Cancer Research UK London Research
Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK. 2 Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard
Medical School, Bldg. 149 13th Street, Charlestown, MA 02129, USA.
Authors for correspondence (e-mails:
Accepted for publication 1 July 2008.
We identify B (PPP2R2A) and B (PPP2R2D), two highly related
membersof the B family of regulatory subunits of the protein phosphatase
PP2A,as important modulators of TGF-β/Activin/Nodal signallingthat
affect the pathway in opposite ways. Knockdown of B inXenopus
embryos or mammalian tissue culture cells suppresses
TGF-β/Activin/Nodal-dependentresponses, whereas knockdown of B
enhances these responses.Moreover, in Drosophila, overexpression of
Smad2 rescues a severewing phenotype caused by overexpression of the single
DrosophilaPP2A B subunit Twins. We show that, in vertebrates,
B enhancesTGF-β/Activin/Nodal signalling by stabilising the basal
levelsof type I receptor, whereas B negatively modulates these
pathwaysby restricting receptor activity. Thus, these highly relatedmembers
of the same subfamily of PP2A regulatory subunits differentiallyregulate
TGF-β/Activin/Nodal signalling to elicit opposingbiological