Biomedical Engineering Reference
In-Depth Information
Wnt WIF-1
Wnt
sFRP
Unliganded state
Liganded state
Extracellular space
Frizzled
Proteasomal
degradation
LRP
Nuclear
localization
Cytoplasm
2.8
Elements of the Wnt/
b
-catenin or canonical pathway. Binding of members of the Wnt cytokine family to Frizzled receptors and
low-density lipoprotein receptor-related protein 5 and 6 (LRP5/6) co-receptors inhibits glycogen synthase kinase 3 (GSK3) through
mechanisms involving the Axin, Frat-1 and Disheveled (Dsh) proteins.
b
-catenin accumulates and is translocated to the nucleus
where it binds to T cell factor/lymphoid enhancer binding factor (TCF/LEF) to cause displacement of transcriptional corepressors
(i.e. silencing mediator of retinoid and thyroid receptors and nuclear receptor corepressor [SMRT/NCoR]) with transcriptional
coactivators (i.e. p300 and cAMP response element-binding protein [p300/CBP]). Wnt signaling can be blocked by interactions of
Wnt with inhibitory factors including Wnt inhibitory factor 1 (WIF-1) and members of the secreted frizzled-related protein (sFRP)
family, or via interaction of LRP5/6 with the Dickkopf (Dkk)/Kremen complex or sclerostin (SOST gene product). The resultant
phosphorylation of
b
-catenin by GSK3 stimulates
b
-catenin degradation (reproduced with permission of the American Society for
Clinical Investigation from Krishnan
et al
.
233
Permission conveyed through Copyright Clearance Center, Inc).
