Description
Wnt signaling pathway plays a central role in the control of embryonic development, tissue regeneration and other physiological processes. Deregulation of the pathway underlies various forms of cancer as well as diseases other than cancer. Several pathways are triggered upon Wnt receptor activation; the canonical, beta-catenin dependent Wnt pathway is the best understood system. The core component of the canonical pathway is the cadherin interacting protein beta-catenin (Ctnnb1), which in the nucleus binds Lef/Hnf1a(Tcf1) transcription factors to turn on the expression of target genes. In the absence of the Wnt signal, cytoplasmic beta-catenin is recruited to the ‘destruction complex’ with axin (which appears to act as a scaffold) and Apc and is phosphorylated on its N-terminal domain by Gsk3b and Csnk1a1. The phosphorylated beta-catenin is recognized by Btrc component of E3 ubiquitin ligase complex and targeted for proteosomal degradation. The interaction of Wnt ligands (19 members in mammals) to frizzled (ten members) and one of two Lrp receptors is antagonized and/or regulated by a number of molecules (eg. Dkk, Sfrp, Wif1). Binding of Wnt to receptors triggers the recruitment of Dvl (disheveled) to the plasma membrane and its interaction with frizzled. Phosphorylation of Lrp by Gsk3b and Csnk1g1 leads to axin binding; the interaction of axin with P-Lrp and possibly Dvl promotes the destabilization of the ‘destruction complex’. Beta-catenin can translocate to the nucleus where it displaces the transcriptional repressor Groucho (Tle) from the Lef1/Hnf1a complex and recruits a number of co-activators. Amongst the target genes of beta-catenin are cell proliferation factors, the protooncogenic myc as well as components of the Wnt pathway.
Abbreviations
Wnt – wingless related family of proteins
Fzd – frizzled homolog family of proteins
Lrp5/6 – low density lipoprotein receptor-related protein 5 or 6
Dvl – disheveled, dsh homolog family of proteins
Ctnnb1 - catenin (cadherin associated protein), beta 1
Axin – axin1 or axin2
Apc - adenomatosis polyposis coli
Gsk3b - glycogen synthase kinase 3 beta
Csnk1a1 - casein kinase 1, alpha 1
Csnk1g1 - casein kinase 1, gamma 1
Btrc - beta-transducin repeat containing protein
Dkk - dickkopf homolog family of proteins
Sfrp - secreted frizzled-related family of proteins
Wif1 - Wnt inhibitory factor 1
Lef1 - lymphoid enhancer binding factor 1
Hnf1a - HNF1 homeobox A
Tle - transducin-like enhancer of split homolog family of proteins
References
PMID:15473860, 16793760, 17081971, 17208432, 18188179, 18164181, 18432252
