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First published online August 12, 2008
doi: 10.1242/10.1242/dev.020842
,
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:
caroline.hill{at}cancer.org.uk;
michael.howell{at}cancer.org.uk)
Accepted 1 July 2008
We identify B
(PPP2R2A) and B
(PPP2R2D), two highly related
members of the B family of regulatory subunits of the protein phosphatase
PP2A, as important modulators of TGF-β/Activin/Nodal signalling that
affect the pathway in opposite ways. Knockdown of B in Xenopus
embryos or mammalian tissue culture cells suppresses
TGF-β/Activin/Nodal-dependent responses, whereas knockdown of B
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,
B enhances TGF-β/Activin/Nodal signalling by stabilising the basal
levels of type I receptor, whereas B negatively modulates these
pathways by restricting receptor activity. Thus, these highly related members
of the same subfamily of PP2A regulatory subunits differentially regulate
TGF-β/Activin/Nodal signalling to elicit opposing biological
outcomes.
Key words: PP2A regulatory B subunits, TGF-β/Activin/Nodal signalling, Xenopus, Drosophila
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