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

Batut, Julie; Schmierer, Bernhard; Cao, Jing; Raftery, Laurel A.; Hill, Caroline S.; Howell, Michael

doi:10.1242/dev.020842

Cited by 70 publications

(62 citation statements)

References 51 publications

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“…By contrast, the Bα subunit of PP2A itself becomes phosphorylated upon binding to TRI (Griswold-Prenner et al, 1998). The function of B subunits in TGFβ signalling seems to be the stabilization of the receptor complex, as both the knockdown of Bα and overexpression of Bδ lead to degradation of the type-I receptor (Batut et al, 2008). Confirming the previous studies, we found an interaction between the PP2A-B subunits and TGFβ type-I and type-II receptors in vivo.…”

Section: Discussionsupporting

confidence: 89%

“…Furthermore, the Bα and Bβ subunits of PP2A bind and become phosphorylated by TGFβRI (Griswold-Prenner et al, 1998). Most recently, Bα and Bδ have been shown to have opposite roles in TGFβ signalling: Bα activates the pathway by stabilizing Activin type-I receptor (ALK4) protein levels whereas Bδ represses the pathway by downregulating ALK4 activity (Batut et al, 2008). Finally, inhibition of PP2A enhances the C-terminal phosphorylation of TGFβ-Smads (Van Berlo et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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PP2A regulates BMP signalling by interacting with BMP receptor complexes and by dephosphorylating both the C-terminus and the linker region of Smad1

Bengtsson

Schwappacher

Roth

et al. 2009

Journal of Cell Science

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Phosphorylation of Smads is a crucial regulatory step in the signal transduction pathway initiated by bone morphogenetic proteins (BMPs). Although the dephosphorylation events terminating the pathway in the nucleus have been characterized, little is known about the dephosphorylation of Smads in the cytoplasm. In a proteomic screen for proteins interacting with the BMP type-II receptor, we found the regulatory Bβ subunit of PP2A. PP2A is one of the major serine/threonine phosphatases involved in cell-cycle regulation and signal transduction. Here, we present data showing that the Bβ subunit of PP2A interacts with both BMP type-I and type-II receptors. Furthermore, we demonstrate that several B subunits can associate with the BMP type-II receptor, independently of the kinase activity of the receptor and the catalytic subunit of PP2A. By contrast, the PP2A catalytic subunit is required for PP2A function at the receptor complex. This function of PP2A is the dephosphorylation of Smad1, mainly in the linker region. PP2A-mediated dephosphorylation of the BMP-Smad linker region leads to increased nuclear translocation of Smads and overall amplification of the BMP signal. Although other phosphatases identified within the BMP pathway are all shown to inhibit signalling, PP2A is the first example for a signalling stimulatory phosphatase within this pathway.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

PP2A regulates BMP signalling by interacting with BMP receptor complexes and by dephosphorylating both the C-terminus and the linker region of Smad1

Bengtsson

Schwappacher

Roth

et al. 2009

Journal of Cell Science

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“…CDK8/9 have access to Smad molecules on the chromatin but not to receptor-activated Smad molecules that fail to engage in transcriptional complexes ). Another fate for activated Smads is C-terminal dephosphorylation, which mediates Smad recycling for new rounds of signaling and thereby links the duration of signaling to the presence of activated TGF-b or BMP receptors (Batut et al 2008;Schmierer et al 2008). However, Smad C-terminal dephosphorylation does not require prior participation of the molecule in transcription.…”

Section: Discussionmentioning

confidence: 99%

A Smad action turnover switch operated by WW domain readers of a phosphoserine code

Aragón

Goerner²,

Zaromytidou³

et al. 2011

Genes Dev.

217

286

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When directed to the nucleus by TGF-b or BMP signals, Smad proteins undergo cyclin-dependent kinase 8/9 (CDK8/9) and glycogen synthase kinase-3 (GSK3) phosphorylations that mediate the binding of YAP and Pin1 for transcriptional action, and of ubiquitin ligases Smurf1 and Nedd4L for Smad destruction. Here we demonstrate that there is an order of events-Smad activation first and destruction later-and that it is controlled by a switch in the recognition of Smad phosphoserines by WW domains in their binding partners. In the BMP pathway, Smad1 phosphorylation by CDK8/9 creates binding sites for the WW domains of YAP, and subsequent phosphorylation by GSK3 switches off YAP binding and adds binding sites for Smurf1 WW domains. Similarly, in the TGF-b pathway, Smad3 phosphorylation by CDK8/9 creates binding sites for Pin1 and GSK3, then adds sites to enhance Nedd4L binding. Thus, a Smad phosphoserine code and a set of WW domain code readers provide an efficient solution to the problem of coupling TGF-b signal delivery to turnover of the Smad signal transducers.

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“…The PP2A phosphatase is also implicated in TGF-b receptor dephosphorylation. Interestingly, the related PP2A subunits Ba and Bd modulate TGF-b signaling in opposite ways; whereas the Ba subunit enhances TGF-b signaling, most likely by stabilizing TbRI, the Bd subunit suppresses TGF-b signaling, most likely by inhibiting the TbRI kinase activity (Griswold-Prenner et al 1998;Petritsch et al 2000;Batut et al 2008).…”

Section: Adam17mentioning

confidence: 99%

Signaling Receptors for TGF-β Family Members

Heldin

Moustakas

2016

Cold Spring Harb Perspect Biol

556

498

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Transforming growth factor b (TGF-b) family members signal via heterotetrameric complexes of type I and type II dual specificity kinase receptors. The activation and stability of the receptors are controlled by posttranslational modifications, such as phosphorylation, ubiquitylation, sumoylation, and neddylation, as well as by interaction with other proteins at the cell surface and in the cytoplasm. Activation of TGF-b receptors induces signaling via formation of Smad complexes that are translocated to the nucleus where they act as transcription factors, as well as via non-Smad pathways, including the Erk1/2, JNK and p38 MAP kinase pathways, and the Src tyrosine kinase, phosphatidylinositol 3 0 -kinase, and Rho GTPases.

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

Cited by 70 publications

References 51 publications

PP2A regulates BMP signalling by interacting with BMP receptor complexes and by dephosphorylating both the C-terminus and the linker region of Smad1

PP2A regulates BMP signalling by interacting with BMP receptor complexes and by dephosphorylating both the C-terminus and the linker region of Smad1

A Smad action turnover switch operated by WW domain readers of a phosphoserine code

Signaling Receptors for TGF-β Family Members

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