Wnt Signaling Pathway Netpath (Homo sapiens)
WNT signal, through the canonical pathway, controls cell fate determination and through the non-canonical pathway controls cell movement and tissue polarity (Katoh et al). The name "wnt" is a fusion of two terms, wg derived from the Drosophila gene wingless (wg) and int derived from the proto-oncogene integration-1, which is the mammalian homolog of wg (Wend et al).
ß-catenin is the key regulated effector of Wnt, involved in canonical signaling (Cadigan et al). Free ß-catenin is bound by a multiprotein "destruction complex". The ß-catenin destruction complex is comprised of ß-catenin, scaffold proteins (APC, AXIN) and serine/threonine kinases that phosphorylate ß-catenin casein kinase 1 (CSNK1A1, CSNK1D, CSNK1E, CSNK1G1) and GSK3B (Katoh et al, Cadigan et al, Sakanaka et al). The sequential phosphorylation of ß-catenin by casein kinase 1 and GSK3 is recognised by an SCF-class E3-ubiquitin ligase, which targets it for polyubiquitination and proteosomal destruction (Cadigan et al).
Canonical WNT signals are transduced through a two-part receptor, a seven-transmembrane Frizzled (FZD) and low density lipoprotein receptor-related protein 5/6 (LRP5/LRP6) to a ß-catenin (CTNNB1) signaling cascade (Katoh et al, Wend et al, Bhanot et al, Pinson et al). On recruitment of deshevelled (DVL1) to FZD and AXIN to LRP6, ß-catenin destruction complex disassembles leading to its stabilization and nuclear accumulation (Katoh et al, Gao et al). Nuclear ß-catenin binds to T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors and Legless family docking protein, BCL9. These activate the transcription of Wnt target genes CCND1, MYC(Katoh et al, Cadigan et al, Pinson et al, Rubinfeld et al, Kramps et al).
Non-canonical WNT signaling diverges downstream after being transduced through FZD family receptors and co-receptors, ROR2 and RYK. This pathway does not involve ß-catenin-mediated gene expression. Small G proteins such as RAC1, RHOA and downstream effectors of RAC including JNK are DVL-dependant effector molecules of the non-canonical pathway (Katoh et al, Gao et al). These have been implicated in cytoskeletal rearrangement (1), dendrite growth (Gao et al, Rosso et al) and control of cell polarity and orientation (Gao et al). Nemo-like kinase (NLK) and nuclear factor of activated T cells (NFAT) are Ca2+-dependant effectors of the non-canonical pathway. NLK inhibits canonical pathway by phosphorylation of TCF/LEF family transcription factors. NFAT transcription factor is implicated in convergent extension during early embryogenesis and carcinogenic metastasis (Gao et al).NetPath (http://www.netpath.org) is a collaborative effort between PandeyLab at Johns Hopkins University (http://pandeylab.igm.jhmi.edu) and Institute of Bioinformatics (http://www.ibioinformatics.org). This version of the pathway is available at NetSlim (http://www.netpath.org/netslim). If you use this pathway, please cite the NetPath website.
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