Abstract
WNT/β-catenin signaling is a highly complex pathway that plays diverse roles in various cellular processes. While WNT ligands usually signal through their dedicated Frizzled receptors, the decision to signal in a β-catenin-dependent or -independent manner rests upon the type of co-receptors used. Canonical WNT signaling is β-catenin-dependent, whereas non-canonical WNT signaling is β-catenin-independent according to the classical definition. This still holds true, albeit with some added complexity, as both the pathways seem to cross-talk with intertwined networks that involve the use of different ligands, receptors, and co-receptors. β-catenin can be directly phosphorylated by various kinases governing its participation in either canonical or non-canonical pathways. Moreover, the co-activators that associate with β-catenin determine the output of the pathway in terms of induction of genes promoting proliferation or differentiation. In this review, we provide an overview of how protein phosphorylation controls WNT/β-catenin signaling, particularly in human cancer.
Highlights
WNT/b-catenin signaling is a tightly controlled and highly conserved pathway that regulates cell fate during embryogenesis, hepatobiliary development, liver homeostasis, repair in adulthood, cell proliferation, differentiation, and cell polarity [1, 2]
WNT is a family of nineteen hydrophobic cysteine-rich secreted glycoproteins which serve as ligands for ten members of the Frizzled (Fz) family of 7transmembrane receptors, the co-receptors low-density lipoprotein receptor-related proteins 5/6 (LRP 5/6), and non-classical WNT receptors like RYK and ROR [4–8]
Like other cellular signaling events, WNT/b-catenin signaling is tightly controlled by protein phosphorylation and dephosphorylation
Summary
WNT/b-catenin signaling is a tightly controlled and highly conserved pathway that regulates cell fate during embryogenesis, hepatobiliary development, liver homeostasis, repair in adulthood, cell proliferation, differentiation, and cell polarity [1, 2]. A more recent study demonstrated that an E3 ubiquitin ligase, tripartite motifcontaining protein 11 (TRIM11), serves as an oncogene in lymphomas by promoting cell proliferation through activation of the b-catenin signaling This regulation is brought about by TRIM11-mediated ubiquitination and degradation of AXIN1, part of the destruction complex of b-catenin [46]. The first branch of the non-canonical pathway – PCP signaling occurs through WNT-Fz receptor interaction without the involvement of LRP5/6 co-receptors This results in activation of the DVL protein, which in turn activates a small GTPase such as RAC [63]. Non-canonical WNT ligands such as WNT5A interact with ROR family orphan receptor tyrosine kinases such as ROR2 to activate JNK, RHOA, etc This has been shown to antagonize the canonical WNT signaling pathway by inhibiting the transcriptional activation potential of the b-catenin/TCF complex, reducing the expression of Cyclin D1 [65, 66]. The antagonism of canonical WNT signaling by non-canonical WNTs involves multiple mechanisms that may or may not involve calcium [71]
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