Wnt signaling: complexity at the surface

Abstract

Wnts are secreted proteins that are essential for a wide array of developmental and physiological processes. They signal across the plasma membrane by interacting with serpentine receptors of the Frizzled (Fz) family and members of the low-density-lipoprotein-related protein (LRP) family. Activation of Fz-LRP promotes the stability and nuclear localization of β-catenin by compromising the ability of a multiprotein complex containing axin, adenomatosis polyposis coli (APC) and glycogen synthase kinase 3 (GSK3) to target it for degradation and block its nuclear import. The Fz-LRP receptor complex probably accomplishes this by generating multiple signals in the cytoplasm. These involve activation of Dishevelled (Dsh), possibly through trimeric G proteins and LRP-mediated axin binding and/or degradation. However, individual Wnts and Fzs can activate both β-catenin-dependent and -independent pathways, and Fz co-receptors such as LRP probably provide some of this specificity. Additional, conflicting data concern the role of the atypical receptor tyrosine kinase Ryk, which might mediate Wnt signaling independently of Fz and/or function as a Fz co-receptor in some cells.

Function and biological roles of the Dickkopf family of Wnt modulators

“…This result supports the idea of two distinct receptor events, mediated by Lrp5/6 and Fz, respectively, which converge on b-catenin (Cadigan and Liu, 2006;Li et al, 2002).…”

“…Wnt/b-catenin pathway (Cadigan and Liu, 2006), (2) the planar cell polarity pathway (PCP), which does not involve b-catenin but recruits small GTPases of the rho/ cdc42 family to activate Jun kinase (JNK) and which at least in vertebrates appears to be triggered by Wnts (Tada et al, 2002) and (3) the Wnt/Ca 2 þ cascade, which is still controversial and may be partly overlapping with the PCP pathway (Kohn and Moon, 2005 (Semenov et al, 2001). This is because Dkks bind and modulate Wnt coreceptors of the lipoprotein receptor-related protein 5/6 class, which are indispensable for routing the Wnt signal to the b-catenin pathway .…”

“…Wnts are an evolutionary conserved family of growth factors, whose signaling is involved in numerous processes in development, in the adult and in disease (Cadigan and Nusse, 1997;Moon et al, 2004;Cadigan and Liu, 2006). Wnts are subject to negative and positive regulation by a wide range on effectors that act either intracellularly to modulate components of the signal transduction machinery, or extracellularly to modulate ligand receptor interactions.…”

Complex Expression Pattern of Wnt Ligands and Frizzled Receptors in Human Placenta and its Trophoblast Subtypes

“…Upon binding β-catenin converts TCFs into transcriptional activators inducing target genes for proliferation and invasion [4,5]. However, Wnts can also bind FZDs independently of LRP, activate or inhibit canonical Wnt signalling depending on the receptor context and induce non-canonical signal transduction pathways involving Ca 2+ as a second messenger [6][7][8].…”

The Role of Glycogen Synthase Kinase 3-β in Immunity and Cell Cycle: Implications in Esophageal Cancer

“…These studies indicate that GSK3b might control the progression of EC by modifying the activation of NF-jB in different stages of tumorigenesis. Numerous studies reported that phospho-inactivation of GSK3b results in the degradation of c-Myc and b-catenin (Cadigan and Liu 2006;Yada et al 2004). b-Catenin is a critical component of adherent junction in stratified squamous epithelium of esophageal.…”