Endofin acts as a Smad anchor for receptor activation in BMP signaling

Shi, Weibin; Chang, Chenbei; Nie, Shuyi; Xie, Shuntao; Wan, Mei; Cao, Xu

doi:10.1242/jcs.03400

Cited by 89 publications

(83 citation statements)

References 29 publications

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“…First, unlike most R-Smad anchors of FYVEcontaining molecules that positively regulate TGF␤/BMP signaling (10,33,34,36), MTMR4 negatively regulates TGF␤ signaling through R-Smads dephosphorylation. Second, unlike most transcription co-factors (12) or phosphatases (17) that interact with Smads in the nucleus, MTMR4 constitutively resides in early endosomes (20) and most likely dephosphorylates Smad2/3 in situ.…”

Section: Discussionmentioning

confidence: 99%

MTMR4 Attenuates Transforming Growth Factor β (TGFβ) Signaling by Dephosphorylating R-Smads in Endosomes

Pan

Qin

et al. 2010

Journal of Biological Chemistry

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Homeostasis of Smad phosphorylation at its C-terminal SXS motif is essential for transforming growth factor ␤ (TGF␤) signaling. Whereas it is known that TGF␤ signaling can be terminated by phosphatases, which dephosphorylate R-Smads in the nucleus, it is unclear whether there are any cytoplasmic phosphatase(s) that can attenuate R-Smad phosphorylation and nuclear translocation. Here we demonstrate that myotubularinrelated protein 4 (MTMR4), a FYVE domain-containing dualspecificity protein phosphatase (DSP), attenuates TGF␤ signaling by reducing the phosphorylation level of R-Smads in early endosomes. Co-immunoprecipitation experiments showed that endogenous MTMR4 interacts with phosphorylated R-Smads, and that this interaction is correlated with dephosphorylation of R-Smads. Further analysis showed that overexpression of MTMR4 resulted in the sequestration of activated Smad3 in the early endosomes, thus reducing its nuclear translocation. However, both point mutations at the conserved catalytic site of the phosphatase (MTMR4-C407S) and small interference RNA of endogenous Mtmr4 expression led to sustained Smad3 activation. This work therefore suggests that MTMR4 plays an important role in preventing the overactivation of TGF␤ signaling by dephosphorylating activated R-Smads that have been trafficked to early endosomes. The transforming growth factor ␤ (TGF␤)3 signaling pathway involves two transmembrane serine/threonine kinases, namely type II (T␤RII) and type I TGF␤ receptors (T␤RI) (1, 2). T␤RII, a constitutively active kinase, binds TGF␤ to initiate its heterodimerization with T␤RI. T␤RI then becomes phosphorylated and activates a signaling cascade through a family of intracellular signaling mediators known as Smads.In doing so, T␤RI recruits receptor-regulated Smads (RSmads, including BMP signaling transducers Smad1, -5, and -8 and TGF␤ signaling transducers Smad2, -3) and phosphorylates the two conserved C-terminal serines (SXS) of R-Smads. Activated R-Smads form a trimeric complex with a common mediator Smad (Co-Smad, Smad4), and these complexes translocate into the nucleus to regulate the transcription of an array of target genes (3-7). Recent studies have also indicated that Smad Anchor for Receptor Activation (SARA), an early endosomal protein containing a characteristic FYVE domain (Fab1p, YO1B, Vac1p, and EEA1), serves as an anchor protein by directly recruiting Smad2 to the early endosomes (8, 9) and presenting Smad2 to the internalized T␤RI/II complex (10, 11). Phosphorylated Smad2 then dissociates from SARA and leaves the early endosome. Subsequently, it forms a Smad2-Smad4 complex for nuclear translocation.Despite the fact that TGF␤ signaling activation is surprisingly simple, there are many layers of negative regulation that fine-tune or terminate the signal. The inhibitory Smads (I-Smads, including Smad6 and -7) competitively inhibit the interaction of R-Smads with Smad4 or receptors to provide a negative checkpoint for TGF␤-signaling activation (12). Ubiquitin-dependent degradation of activated...

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Section: Discussionmentioning

confidence: 99%

MTMR4 Attenuates Transforming Growth Factor β (TGFβ) Signaling by Dephosphorylating R-Smads in Endosomes

Pan

Qin

et al. 2010

Journal of Biological Chemistry

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“…SARA cooperates with the cytoplasmic promyelocytic leukemia (cPML) tumor suppressor protein (Lin et al 2004) and with the adaptor protein disabled-2 (DAB2) (Hocevar et al 2001), which stabilize the complex. In an analogous manner, endofin acts as an anchor for Smad1 in signaling via BMP receptors (Shi et al 2007). In the rest of this section, we will focus on TGF-b receptor endocytosis, which is best understood.…”

Section: Tgf-b Receptor Regulation By Endocytosismentioning

confidence: 99%

Signaling Receptors for TGF-β Family Members

Heldin

Moustakas

2016

Cold Spring Harb Perspect Biol

575

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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“…However, unlike SARA or Hrs, endofin binds to Smad4 and, in cooperation with SARA, may assist the heterocomplex formation between receptor-phosphorylated Smad2/3 and Smad4 [75] (Figure 3). Endofin has also been suggested to promote BMP signaling by helping recruit Smad1 to BMP receptors [78]. In this regard, endofin acts very similarly as SARA to function as a Smad anchor for receptor activation.…”

Section: Tgf-β Signaling In Endosomesmentioning

confidence: 99%

“…SARA can bring the catalytic subunit of protein phosphatase 1 to and dephosphorylate the Dpp receptor Thickveins (Tkv) [79], whereas loss of Hrs leads to enhanced Dpp signaling and an increased level of Tkv [80]. Interestingly, endofin has been suggested to recruit protein phosphatase 1 to dephosphorylate BMP type I receptors and therefore attenuate BMP signaling [78]. It is currently unknown how the opposite functions of endofin in BMP signaling are controlled.…”

Section: Tgf-β Signaling In Endosomesmentioning

confidence: 99%