Wnt-signaling is a regulator of a number of endocrine functions in health and disease. Wnt signaling molecules are expressed in the human endocrine pancreas and regulate insulin secretion, crosstalk between adipocytes and endocrine cells and the proliferation of pancreas β-cells. Wnt can bind to cell-surface receptors called frizzled and to lipoprotein receptor-related protein co-receptors (e.g. LRP5). Upon binding to frizzled and LFP5 co-receptors dishelved is activated and subsequently recruits the axin-APC-GSK3β complex to the cell membrane. The result is an inhibition of GSK3β phosphorylation of beta-catenin which then allows beta-catenin to form the bipartite beta-catenin/TCF transcription factor enhancing expression of Wnt target genes. Transcription factor 7–like 2 (TCF7L2, also known as TCF4), a member of the WNT signaling pathway, is a type 2 diabetes susceptibility gene and of all known polymorphisms, those of TCF7L2 have the greatest association with the risk of developing type 2 diabetes. Polymorphisms of WNT5B are also associated with high risk for type 2 diabetes.
Wnts are also important for adipogenesis and crosstalk between adipocytes and endocrine cells. Constitutive endogeneous Wnt-signaling keeps pre-adipocytes undifferentiated. In addition to these autocrine and paracrine functions, Wnt molecules secreted by adipocytes (such as Wnt3a and Wnt10b) can induce transcription of the StAR gene which leads to increased aldosterone and cortisol release from adrenocortical cells which affects arterial hypertension. It has also been shown that nuclear accumulation of beta-catenin may be associated with the adrenal tumorigenesis and the proliferative activity of these neoplasms.
GSK-3/Wnt Signaling Subcategories