Hartman Institute for Therapeutic Organ Regeneration

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

TitleTMEM88 Inhibits Wnt Signaling by Promoting Wnt Signalosome Localization to Multivesicular Bodies.
Publication TypeJournal Article
Year of Publication2019
AuthorsLee H, Evans T
JournaliScience
Volume19
Pagination267-280
Date Published2019 Sep 27
ISSN2589-0042
Abstract

<p>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.</p>

DOI10.1016/j.isci.2019.07.039
Alternate JournaliScience
PubMed ID31401350
PubMed Central IDPMC6700443
Grant ListR35 HL135778 / HL / NHLBI NIH HHS / United States

Weill Cornell Medicine
Hartman Institute for Therapeutic Organ Regeneration
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