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

ABSTRACT: 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.

SUBMITTER: Batut J

PROVIDER: S-EPMC4940033 | biostudies-other | 2008 Sep

REPOSITORIES: biostudies-other

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

Batut Julie J Schmierer Bernhard B Cao Jing J Raftery Laurel A LA Hill Caroline S CS Howell Michael M

Development (Cambridge, England) 20080901 17

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 ...[more]

PMID: 18697906

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Project description:Large conductance calcium-activated potassium (BK) channels play a key role in the control of neuronal activity. Ethanol is a potent activator of BK channel gating, but how this action may impact ethanol drinking still remains poorly understood. Auxiliary ? subunits are known to modulate ethanol-induced potentiation of BK currents. In the present study, we investigated whether BK ?1 and ?4 subunits influence voluntary ethanol consumption using knockout (KO) mice. In a first experiment, mice were first subjected to continuous two-bottle choice (2BC) and were then switched to intermittent 2BC, which progressively increased ethanol intake as previously described in wildtype mice. BK ?1 or ?4 subunit deficiency did not affect ethanol self-administration under either schedule of access. In a second experiment, mice were first trained to drink ethanol in a limited-access 2BC paradigm. BK ?1 or ?4 deletion did not affect baseline consumption. Weeks of 2BC were then alternated with weeks of chronic intermittent ethanol (CIE) or air inhalation. As expected, a gradual escalation of ethanol drinking was observed in dependent wildtype mice, while intake remained stable in non-dependent wildtype mice. However, CIE exposure only produced a mild augmentation of ethanol consumption in BK ?4 KO mice. Conversely, ethanol drinking increased after fewer CIE cycles in BK ?1 KO mice than in wildtype mice. In conclusion, BK ?1 or ?4 did not influence voluntary ethanol drinking in non-dependent mice, regardless of the pattern of access to ethanol. However, deletion of BK ?4 attenuated, while deletion of BK ?1 accelerated, the escalation of ethanol drinking during withdrawal from CIE. Our data suggest that BK ?1 and ?4 subunits have an opposite influence on the negative reinforcing properties of ethanol withdrawal. Modulating the expression, distribution or interactions of BK channel auxiliary subunits may therefore represent a novel avenue for the treatment of alcoholism.

Dataset Information

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

Publications

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

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