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Development 135 (17): 2927-2937

Two highly related regulatory subunits of PP2A exert opposite effects on TGF-β/Activin/Nodal signalling

Julie Batut1,*,{dagger}, Bernhard Schmierer1,*, Jing Cao2, Laurel A. Raftery2, Caroline S. Hill1,§, and Michael Howell1,{ddagger},§

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 for publication 1 July 2008.

Abstract: We identify B{alpha} (PPP2R2A) and B{delta} (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{alpha} in Xenopus embryos or mammalian tissue culture cells suppresses TGF-β/Activin/Nodal-dependent responses, whereas knockdown of B{delta} 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{alpha} enhances TGF-β/Activin/Nodal signalling by stabilising the basal levels of type I receptor, whereas B{delta} 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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