TMEM88 Inhibits Wnt Signaling by Promoting Wnt Signalosome Localization to Multivesicular Bodies

Wnt/β-catenin signaling is regulated in a bimodal fashion during cardiogenesis. Signaling is initially required to promote generation of precardiac mesoderm, but subsequently must be repressed for cardiac progenitor specification. TMEM88 was discovered recently as a negative regulator during the lat...

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Published iniScience Vol. 19; pp. 267 - 280
Main Authors Lee, Heejin, Evans, Todd
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 27.09.2019
Elsevier
Subjects
Cell Biology
Molecular Mechanism of Behavior
Stem Cells Research
Molecular Mechanism of Behavior
Stem Cells Research
Cell Biology
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Abstract Wnt/β-catenin signaling is regulated in a bimodal fashion during cardiogenesis. Signaling is initially required to promote generation of precardiac mesoderm, but subsequently must be repressed for cardiac progenitor specification. TMEM88 was discovered recently as a negative regulator during the later phase of cardiac progenitor specification, but how TMEM88 functions was unknown. Based on a C-terminal PDZ-binding motif, TMEM88 was proposed to act by targeting the PDZ domain of Dishevelled, the positive Wnt signaling mediator. However, we discovered that TMEM88 acts downstream of the β-catenin destruction complex and can inhibit Wnt signaling independent of Dishevelled. TMEM88 requires the PDZ-binding motif for trafficking from Golgi to the plasma membrane and is also found in the multivesicular body (MVB) associated with the endocytosed Wnt signalosome. Expression of Tmem88 promotes association of the Wnt signalosome including β-catenin to the MVB, leading to reduced accumulation of nuclear β-catenin and repression of Wnt signaling. [Display omitted] •Human ESCs with a targeted TMEM88 knockout are impaired for cardiac specification•TMEM88 does not require Dishevelled to inhibit Wnt signaling•TMEM88 is trafficked from Golgi to plasma membrane and then to the MVB•Expression of TMEM88 promotes association of the signalosome to the MVB Molecular Mechanism of Behavior; Cell Biology; Stem Cells Research
AbstractList Wnt/β-catenin signaling is regulated in a bimodal fashion during cardiogenesis. Signaling is initially required to promote generation of precardiac mesoderm, but subsequently must be repressed for cardiac progenitor specification. TMEM88 was discovered recently as a negative regulator during the later phase of cardiac progenitor specification, but how TMEM88 functions was unknown. Based on a C-terminal PDZ-binding motif, TMEM88 was proposed to act by targeting the PDZ domain of Dishevelled, the positive Wnt signaling mediator. However, we discovered that TMEM88 acts downstream of the β-catenin destruction complex and can inhibit Wnt signaling independent of Dishevelled. TMEM88 requires the PDZ-binding motif for trafficking from Golgi to the plasma membrane and is also found in the multivesicular body (MVB) associated with the endocytosed Wnt signalosome. Expression of Tmem88 promotes association of the Wnt signalosome including β-catenin to the MVB, leading to reduced accumulation of nuclear β-catenin and repression of Wnt signaling. • Human ESCs with a targeted TMEM88 knockout are impaired for cardiac specification • TMEM88 does not require Dishevelled to inhibit Wnt signaling • TMEM88 is trafficked from Golgi to plasma membrane and then to the MVB • Expression of TMEM88 promotes association of the signalosome to the MVB Molecular Mechanism of Behavior; Cell Biology; Stem Cells Research
Wnt/β-catenin signaling is regulated in a bimodal fashion during cardiogenesis. Signaling is initially required to promote generation of precardiac mesoderm, but subsequently must be repressed for cardiac progenitor specification. TMEM88 was discovered recently as a negative regulator during the later phase of cardiac progenitor specification, but how TMEM88 functions was unknown. Based on a C-terminal PDZ-binding motif, TMEM88 was proposed to act by targeting the PDZ domain of Dishevelled, the positive Wnt signaling mediator. However, we discovered that TMEM88 acts downstream of the β-catenin destruction complex and can inhibit Wnt signaling independent of Dishevelled. TMEM88 requires the PDZ-binding motif for trafficking from Golgi to the plasma membrane and is also found in the multivesicular body (MVB) associated with the endocytosed Wnt signalosome. Expression of Tmem88 promotes association of the Wnt signalosome including β-catenin to the MVB, leading to reduced accumulation of nuclear β-catenin and repression of Wnt signaling.Wnt/β-catenin signaling is regulated in a bimodal fashion during cardiogenesis. Signaling is initially required to promote generation of precardiac mesoderm, but subsequently must be repressed for cardiac progenitor specification. TMEM88 was discovered recently as a negative regulator during the later phase of cardiac progenitor specification, but how TMEM88 functions was unknown. Based on a C-terminal PDZ-binding motif, TMEM88 was proposed to act by targeting the PDZ domain of Dishevelled, the positive Wnt signaling mediator. However, we discovered that TMEM88 acts downstream of the β-catenin destruction complex and can inhibit Wnt signaling independent of Dishevelled. TMEM88 requires the PDZ-binding motif for trafficking from Golgi to the plasma membrane and is also found in the multivesicular body (MVB) associated with the endocytosed Wnt signalosome. Expression of Tmem88 promotes association of the Wnt signalosome including β-catenin to the MVB, leading to reduced accumulation of nuclear β-catenin and repression of Wnt signaling.
Wnt/β-catenin signaling is regulated in a bimodal fashion during cardiogenesis. Signaling is initially required to promote generation of precardiac mesoderm, but subsequently must be repressed for cardiac progenitor specification. TMEM88 was discovered recently as a negative regulator during the later phase of cardiac progenitor specification, but how TMEM88 functions was unknown. Based on a C-terminal PDZ-binding motif, TMEM88 was proposed to act by targeting the PDZ domain of Dishevelled, the positive Wnt signaling mediator. However, we discovered that TMEM88 acts downstream of the β-catenin destruction complex and can inhibit Wnt signaling independent of Dishevelled. TMEM88 requires the PDZ-binding motif for trafficking from Golgi to the plasma membrane and is also found in the multivesicular body (MVB) associated with the endocytosed Wnt signalosome. Expression of Tmem88 promotes association of the Wnt signalosome including β-catenin to the MVB, leading to reduced accumulation of nuclear β-catenin and repression of Wnt signaling. : Molecular Mechanism of Behavior; Cell Biology; Stem Cells Research Subject Areas: Molecular Mechanism of Behavior, Cell Biology, Stem Cells Research
Wnt/β-catenin signaling is regulated in a bimodal fashion during cardiogenesis. Signaling is initially required to promote generation of precardiac mesoderm, but subsequently must be repressed for cardiac progenitor specification. TMEM88 was discovered recently as a negative regulator during the later phase of cardiac progenitor specification, but how TMEM88 functions was unknown. Based on a C-terminal PDZ-binding motif, TMEM88 was proposed to act by targeting the PDZ domain of Dishevelled, the positive Wnt signaling mediator. However, we discovered that TMEM88 acts downstream of the β-catenin destruction complex and can inhibit Wnt signaling independent of Dishevelled. TMEM88 requires the PDZ-binding motif for trafficking from Golgi to the plasma membrane and is also found in the multivesicular body (MVB) associated with the endocytosed Wnt signalosome. Expression of Tmem88 promotes association of the Wnt signalosome including β-catenin to the MVB, leading to reduced accumulation of nuclear β-catenin and repression of Wnt signaling.
Wnt/β-catenin signaling is regulated in a bimodal fashion during cardiogenesis. Signaling is initially required to promote generation of precardiac mesoderm, but subsequently must be repressed for cardiac progenitor specification. TMEM88 was discovered recently as a negative regulator during the later phase of cardiac progenitor specification, but how TMEM88 functions was unknown. Based on a C-terminal PDZ-binding motif, TMEM88 was proposed to act by targeting the PDZ domain of Dishevelled, the positive Wnt signaling mediator. However, we discovered that TMEM88 acts downstream of the β-catenin destruction complex and can inhibit Wnt signaling independent of Dishevelled. TMEM88 requires the PDZ-binding motif for trafficking from Golgi to the plasma membrane and is also found in the multivesicular body (MVB) associated with the endocytosed Wnt signalosome. Expression of Tmem88 promotes association of the Wnt signalosome including β-catenin to the MVB, leading to reduced accumulation of nuclear β-catenin and repression of Wnt signaling. [Display omitted] •Human ESCs with a targeted TMEM88 knockout are impaired for cardiac specification•TMEM88 does not require Dishevelled to inhibit Wnt signaling•TMEM88 is trafficked from Golgi to plasma membrane and then to the MVB•Expression of TMEM88 promotes association of the signalosome to the MVB Molecular Mechanism of Behavior; Cell Biology; Stem Cells Research
Author Lee, Heejin
Evans, Todd
AuthorAffiliation 1 Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA
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Snippet Wnt/β-catenin signaling is regulated in a bimodal fashion during cardiogenesis. Signaling is initially required to promote generation of precardiac mesoderm,...
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SubjectTerms Cell Biology
Molecular Mechanism of Behavior
Stem Cells Research
Title TMEM88 Inhibits Wnt Signaling by Promoting Wnt Signalosome Localization to Multivesicular Bodies
URI https://dx.doi.org/10.1016/j.isci.2019.07.039
https://www.ncbi.nlm.nih.gov/pubmed/31401350
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