Dickkopf-1: an emerging danger signal in hypertension and cardiovascular disease

Graphical Abstract Graphical Abstract Canonical Wnt signalling pathway. A Wnt protein binds to Frizzled, a transmembrane protein. LDL-like receptor 5/6 is a co-receptor for Wnt binding. Once the Wnt–Frizzled–LRP 5/6 complex forms, this activates Dishevelled which phosphorylates LRP 5/6. This destabi...

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Bibliographic Details
Published in:European heart journal 2024-03, Vol.45 (9), p.704-706
Main Author: Toth, Peter P
Format: Article
Language:English
Subjects:
Cardiovascular Diseases
Humans
Hypertension
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Summary:Graphical Abstract Graphical Abstract Canonical Wnt signalling pathway. A Wnt protein binds to Frizzled, a transmembrane protein. LDL-like receptor 5/6 is a co-receptor for Wnt binding. Once the Wnt–Frizzled–LRP 5/6 complex forms, this activates Dishevelled which phosphorylates LRP 5/6. This destabilizes the β-catenin destruction complex comprised of adenomatous polyposis coli, glycogen synthase 3β, casein kinase-1, and axin. This allows for the accumulation of β-catenin in the cytosol which then translocates into the nucleus and activates the transcriptional factors T-cell factor and lymphoid enhancer factor, activating the expression of specific genes. In the presence of DKK-1, the LRP 5/6 co-receptor cannot interact with Frizzled, and instead binds to Kremen. The Kremen–DKK-1–LRP 5/6 complex undergoes endocytosis. The β-catenin destruction complex remains intact and phosphorylates β-catenin, which then undergoes ubiquitination and is shunted to the proteasome for destruction. Nuclear gene expression is not activated. In the model developed by Ma et al.,15 DKK-1 prevents LRP 5/6 from antagonizing AT1R (another transmembrane protein) because it undergoes clearance from the cell membrane via endocytosis. The lower panel summarizes some of the known adverse effects of DKK-1 on the cardiovascular system.
ISSN:0195-668X
1522-9645
DOI:10.1093/eurheartj/ehad797