Chemical Genetics Reveals a Role of Squalene Synthase in TGFβ Signaling and Cardiomyogenesis

KY02111 is a widely used small molecule that boosts cardiomyogenesis of the mesoderm cells derived from pluripotent stem cells, yet its molecular mechanism of action remains elusive. The present study resolves the initially perplexing effects of KY02111 on Wnt signaling and subsequently identifies s...

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Bibliographic Details
Published in:Angewandte Chemie 2021-09, Vol.133 (40), p.21995-22002
Main Authors: Takemoto, Yasushi, Kadota, Shin, Minami, Itsunari, Otsuka, Shinya, Okuda, Satoshi, Abo, Masahiro, Punzalan, Louvy Lynn, Shen, Yan, Shiba, Yuji, Uesugi, Motonari
Format: Article
Language:English
Subjects:
cardiomyogenesis
Cardiomyopathy
Cardiovascular diseases
chemical genetics
Chemistry
Coronary artery disease
Genetics
Heart diseases
Kinases
Membrane proteins
Mesoderm
Mutation
Myocardium
Pluripotency
Signaling
Smad protein
SQS
Squalene
Stem cells
TGFβ signaling
Ventricle
Wnt protein
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Summary:KY02111 is a widely used small molecule that boosts cardiomyogenesis of the mesoderm cells derived from pluripotent stem cells, yet its molecular mechanism of action remains elusive. The present study resolves the initially perplexing effects of KY02111 on Wnt signaling and subsequently identifies squalene synthase (SQS) as a molecular target of KY02111 and its optimized version, KY‐I. By disrupting the interaction of SQS with cardiac ER‐membrane protein TMEM43, KY02111 impairs TGFβ signaling, but not Wnt signaling, and thereby recapitulates the clinical mutation of TMEM43 that causes arrhythmogenic right ventricular cardiomyopathy (ARVC), an inherited heart disease that involves a substitution of myocardium with fatty tissue. These findings reveal a heretofore undescribed role of SQS in TGFβ signaling and cardiomyogenesis. KY02111 may find its use in ARVC modeling as well as serve as a chemical tool for studying TGFβ/SMAD signaling. KY02111 is a widely used small molecule that boosts cardiomyogenesis. Chemical genetics of KY02111 identified squalene synthase (SQS) as a molecular target of KY02111. By disrupting the interaction of SQS with cardiac ER‐membrane protein TMEM43, KY02111 impairs TGFβ/SMAD signaling and recapitulates the clinical mutation of TMEM43 that causes an inherited heart disease.
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.202100523