WNT signal, through the canonical pathway, controls cell fate determination and through the non-canonical pathway controls cell movement and tissue polarity (1). 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 (2).
ß-catenin is the key regulated effector of Wnt, involved in canonical signaling (3). 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 (1, 3, 4). 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 (3).
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 (1, 2, 5, 6). On recruitment of deshevelled (DVL1) to FZD and AXIN to LRP6, ß-catenin destruction complex disassembles leading to its stabilization and nuclear accumulation (1, 7). 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(1, 3, 6, 8, 9).
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 (1, 7). These have been implicated in cytoskeletal rearrangement (1), dendrite growth (7, 10) and control of cell polarity and orientation (7). 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 (7).
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10. Rosso SB, Sussman D, Wynshaw-Boris A, Salinas PC (2005) Wnt signaling through Dishevelled, Rac and JNK regulates dendritic development. Nat Neurosci, 8(1): 34-42.