XB-ART-39724
Mol Biol Cell
July 1, 2009;
20
(14):
3436-50.
Tumor necrosis factor-receptor-associated factor-4 is a positive regulator of transforming growth factor-beta signaling that affects neural crest formation.
Kalkan T
,
Iwasaki Y
,
Park CY
,
Thomsen GH
.
Abstract
The transforming growth factor (TGF)-beta superfamily regulates cell proliferation, apoptosis, differentiation, migration, and development. Canonical TGFbeta signals are transduced to the nucleus via Smads in both major signaling branches, bone morphogenetic protein (BMP) or Activin/Nodal/TGFbeta. Smurf ubiquitin (Ub) ligases attenuate these pathways by targeting Smads and other signaling components for degradation by the 26S proteasome. Here, we identify tumor necrosis factor (TNF)-receptor-associated factor-4 (TRAF4) as a new target of Smurf1, which polyubiquitylates TRAF4 to trigger its proteasomal destruction. Unlike other TRAF family members, which mediate signal transduction by TNF, interleukin, or Toll-like receptors, we find that TRAF4 potentiates BMP and Nodal signaling. In the frog Xenopus laevis, TRAF4 mRNA is stored maternally in the egg animal pole, and in the embryo it is expressed in the gastrula marginal zone, neural plate, and cranial and trunk neural crest. Knockdown of embryonic TRAF4 impairs signaling, neural crest development and neural folding, whereas TRAF4 overexpression boosts signaling and expands the neural crest. In human embryonic kidney 293 cells, small interfering RNA knockdown of Smurf1 elevates TRAF4 levels, indicating endogenous regulation of TRAF4 by Smurf1. Our results uncover new functions for TRAF4 as a Smurf1-regulated mediator of BMP and Nodal signaling that are essential for neural crest development and neural plate morphogenesis.
PubMed ID: 19458200
PMC ID: PMC2710828
Article link: Mol Biol Cell
Grant support: [+]
Species referenced: Xenopus laevis
Genes referenced: bmp4 chrd.1 foxd3 myc nodal nodal1 nodal2 nog odc1 smurf1 snai2 sox10 tgfb1 tnf traf4
Morpholinos: traf4 MO1 traf4 MO2 traf4 MO3
Article Images: [+] show captions
References [+] :
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Wu, Subcellular targeting of oxidants during endothelial cell migration. 2005, Pubmed
Xu, Involvement of TRAF4 in oxidative activation of c-Jun N-terminal kinase. 2002, Pubmed
Xu, Vinculin knockout results in heart and brain defects during embryonic development. 1998, Pubmed
Yamashita, TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-beta. 2008, Pubmed
Ye, TRAF family proteins interact with the common neurotrophin receptor and modulate apoptosis induction. 1999, Pubmed
Ying, Smurf1 facilitates myogenic differentiation and antagonizes the bone morphogenetic protein-2-induced osteoblast conversion by targeting Smad5 for degradation. 2003, Pubmed
Yokota, A novel role for a nodal-related protein; Xnr3 regulates convergent extension movements via the FGF receptor. 2003, Pubmed , Xenbase
Zhang, Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. 2001, Pubmed , Xenbase
Zhao, E3 ubiquitin ligase Smurf1 mediates core-binding factor alpha1/Runx2 degradation and plays a specific role in osteoblast differentiation. 2003, Pubmed
Zhu, A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. 1999, Pubmed , Xenbase
Abell, MEKK4 is an effector of the embryonic TRAF4 for JNK activation. 2005, Pubmed
Aggarwal, Signalling pathways of the TNF superfamily: a double-edged sword. 2003, Pubmed
Alexandrova, Smurf1 regulates neural patterning and folding in Xenopus embryos by antagonizing the BMP/Smad1 pathway. 2006, Pubmed , Xenbase
Attisano, Signal transduction by the TGF-beta superfamily. 2002, Pubmed
Barth, Bmp activity establishes a gradient of positional information throughout the entire neural plate. 1999, Pubmed
Bastidas, Identification of neural crest competence territory: role of Wnt signaling. 2003, Pubmed , Xenbase
Birsoy, Vg 1 is an essential signaling molecule in Xenopus development. 2005, Pubmed , Xenbase
Bonni, TGF-beta induces assembly of a Smad2-Smurf2 ubiquitin ligase complex that targets SnoN for degradation. 2001, Pubmed
Brouns, The adhesion signaling molecule p190 RhoGAP is required for morphogenetic processes in neural development. 2000, Pubmed
Carpentier, Smurf2 is a TRAF2 binding protein that triggers TNF-R2 ubiquitination and TNF-R2-induced JNK activation. 2008, Pubmed
Cherfils-Vicini, Characterization of immune functions in TRAF4-deficient mice. 2008, Pubmed
Chung, All TRAFs are not created equal: common and distinct molecular mechanisms of TRAF-mediated signal transduction. 2002, Pubmed
Crane, Neural crest stem and progenitor cells. 2006, Pubmed
De Robertis, Dorsal-ventral patterning and neural induction in Xenopus embryos. 2004, Pubmed , Xenbase
Dempsey, The signaling adaptors and pathways activated by TNF superfamily. 2003, Pubmed
Ebisawa, Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation. 2001, Pubmed
Esparza, TRAF4 functions as an intermediate of GITR-induced NF-kappaB activation. 2004, Pubmed
Glavic, Interplay between Notch signaling and the homeoprotein Xiro1 is required for neural crest induction in Xenopus embryos. 2003, Pubmed , Xenbase
Glavic, Role of BMP signaling and the homeoprotein Iroquois in the specification of the cranial placodal field. 2004, Pubmed , Xenbase
Graff, Studies with a Xenopus BMP receptor suggest that ventral mesoderm-inducing signals override dorsal signals in vivo. 1994, Pubmed , Xenbase
Haigo, Shroom induces apical constriction and is required for hingepoint formation during neural tube closure. 2003, Pubmed , Xenbase
Harland, In situ hybridization: an improved whole-mount method for Xenopus embryos. 1992, Pubmed , Xenbase
Harris, Lineage specification in neural crest cell pathfinding. 2006, Pubmed
Hayata, Expression of Brachyury-like T-box transcription factor, Xbra3 in Xenopus embryo. 1999, Pubmed , Xenbase
Hong, Fgf8a induces neural crest indirectly through the activation of Wnt8 in the paraxial mesoderm. 2008, Pubmed , Xenbase
Kavsak, Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. 2001, Pubmed , Xenbase
Kedinger, TRAF4, the unique family member. 2007, Pubmed
Kofron, The role of maternal axin in patterning the Xenopus embryo. 2001, Pubmed , Xenbase
Koleske, Essential roles for the Abl and Arg tyrosine kinases in neurulation. 1999, Pubmed
Kédinger, Tumor necrosis factor receptor-associated factor 4 is a dynamic tight junction-related shuttle protein involved in epithelium homeostasis. 2008, Pubmed
LaBonne, Neural crest induction in Xenopus: evidence for a two-signal model. 1998, Pubmed , Xenbase
Lanier, Mena is required for neurulation and commissure formation. 1999, Pubmed
Le Douarin, Multipotentiality of the neural crest. 2003, Pubmed
Li, Acute tumor necrosis factor alpha signaling via NADPH oxidase in microvascular endothelial cells: role of p47phox phosphorylation and binding to TRAF4. 2005, Pubmed
Lin, Smurf2 is a ubiquitin E3 ligase mediating proteasome-dependent degradation of Smad2 in transforming growth factor-beta signaling. 2001, Pubmed
Marchant, The inductive properties of mesoderm suggest that the neural crest cells are specified by a BMP gradient. 1998, Pubmed , Xenbase
Mayor, Induction of the prospective neural crest of Xenopus. 1995, Pubmed , Xenbase
Monsoro-Burq, Neural crest induction by paraxial mesoderm in Xenopus embryos requires FGF signals. 2003, Pubmed , Xenbase
Monsoro-Burq, Msx1 and Pax3 cooperate to mediate FGF8 and WNT signals during Xenopus neural crest induction. 2005, Pubmed , Xenbase
Morén, Degradation of the tumor suppressor Smad4 by WW and HECT domain ubiquitin ligases. 2005, Pubmed
Murakami, Cooperative inhibition of bone morphogenetic protein signaling by Smurf1 and inhibitory Smads. 2003, Pubmed , Xenbase
Nelson, Cdc42 Effector Protein 2 (XCEP2) is required for normal gastrulation and contributes to cellular adhesion in Xenopus laevis. 2004, Pubmed , Xenbase
Nguyen, Ventral and lateral regions of the zebrafish gastrula, including the neural crest progenitors, are established by a bmp2b/swirl pathway of genes. 1998, Pubmed , Xenbase
Oelgeschläger, Chordin is required for the Spemann organizer transplantation phenomenon in Xenopus embryos. 2003, Pubmed , Xenbase
Oelgeschläger, Identification of a second Xenopus twisted gastrulation gene. 2004, Pubmed , Xenbase
Ozdamar, Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. 2005, Pubmed
Rozan, Identification and characterization of proteins interacting with Traf4, an enigmatic p53 target. 2006, Pubmed
Régnier, Impaired neural tube closure, axial skeleton malformations, and tracheal ring disruption in TRAF4-deficient mice. 2002, Pubmed
Saint-Jeannet, Regulation of dorsal fate in the neuraxis by Wnt-1 and Wnt-3a. 1998, Pubmed , Xenbase
Sapkota, Balancing BMP signaling through integrated inputs into the Smad1 linker. 2007, Pubmed , Xenbase
Shen, Smad6 interacts with Runx2 and mediates Smad ubiquitin regulatory factor 1-induced Runx2 degradation. 2006, Pubmed
Shen, Nodal signaling: developmental roles and regulation. 2007, Pubmed
Shi, Mechanisms of TGF-beta signaling from cell membrane to the nucleus. 2003, Pubmed
Siegel, Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. 2003, Pubmed
Sorrentino, The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner. 2008, Pubmed
Suzuki, Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membrane. 2002, Pubmed
Takeshita, TRAF4 acts as a silencer in TLR-mediated signaling through the association with TRAF6 and TRIF. 2005, Pubmed
Taylor, Modulating the activity of neural crest regulatory factors. 2007, Pubmed , Xenbase
Turner, Expression of achaete-scute homolog 3 in Xenopus embryos converts ectodermal cells to a neural fate. 1994, Pubmed , Xenbase
Villanueva, Posteriorization by FGF, Wnt, and retinoic acid is required for neural crest induction. 2002, Pubmed , Xenbase
Vonica, An obligatory caravanserai stop on the silk road to neural induction: inhibition of BMP/GDF signaling. 2006, Pubmed , Xenbase
Waite, From developmental disorder to heritable cancer: it's all in the BMP/TGF-beta family. 2003, Pubmed
Wang, Regulation of cell polarity and protrusion formation by targeting RhoA for degradation. 2003, Pubmed , Xenbase
Wawersik, Conditional BMP inhibition in Xenopus reveals stage-specific roles for BMPs in neural and neural crest induction. 2004, Pubmed , Xenbase
Wu, Subcellular targeting of oxidants during endothelial cell migration. 2005, Pubmed
Xu, Involvement of TRAF4 in oxidative activation of c-Jun N-terminal kinase. 2002, Pubmed
Xu, Vinculin knockout results in heart and brain defects during embryonic development. 1998, Pubmed
Yamashita, TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-beta. 2008, Pubmed
Ye, TRAF family proteins interact with the common neurotrophin receptor and modulate apoptosis induction. 1999, Pubmed
Ying, Smurf1 facilitates myogenic differentiation and antagonizes the bone morphogenetic protein-2-induced osteoblast conversion by targeting Smad5 for degradation. 2003, Pubmed
Yokota, A novel role for a nodal-related protein; Xnr3 regulates convergent extension movements via the FGF receptor. 2003, Pubmed , Xenbase
Zhang, Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. 2001, Pubmed , Xenbase
Zhao, E3 ubiquitin ligase Smurf1 mediates core-binding factor alpha1/Runx2 degradation and plays a specific role in osteoblast differentiation. 2003, Pubmed
Zhu, A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. 1999, Pubmed , Xenbase