Phosphorylation-Dependent Regulation of WNT/Beta-Catenin Signaling

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.

WNT/β‐catenin pathway is a key regulator of cardiac function and energetic metabolism

“…55 PKCδ phosphorylates βcatenin at Ser715 and targets it for β-Trcp-independent ubiquitination and degradation. 56,57 Protein kinase A (Ser-552 and Ser-675), c-Jun N-terminal kinase 2 ([JNK-2], Ser191 and Ser605), p21-activated kinase (Ser675), and Akt (Ser552) phosphorylate βcatenin and enhance its transcriptional activity. [58][59][60][61] Moreover, Src (Tyr86, Tyr142, and Tyr654) and receptor tyrosine kinases (Tyr142) phosphorylate βcatenin at multiple sites and stimulate its dissociation from cadherins and αcatenin and release from adhesion complexes.…”

“…62,63 Src and receptor tyrosine kinases also promote its interaction with nuclear partners, but protein kinase D1 phosphorylates (Thr112 and Thr120) and stimulates βcatenin interactions with αcatenin and cadherins. 56,[64][65][66] F I G U R E 1 WNT/β-catenin signaling pathway in cardiomyocytes. (A) In unstimulated cells, WNT/β-catenin signaling is inactive, and the cytoplasmic βcatenin pool is sequestered in the destruction complex that undergoes permanent phosphorylation and degradation.…”

“…Interestingly, protein kinase Cζ (PKCζ) phosphorylates β‐catenin at Ser45 and independently on CK1 primes β‐catenin for GSK3β 55 . PKCδ phosphorylates β‐catenin at Ser715 and targets it for β‐Trcp‐independent ubiquitination and degradation 56,57 . Protein kinase A (Ser‐552 and Ser‐675), c‐Jun N‐terminal kinase 2 ([JNK‐2], Ser191 and Ser605), p21‐activated kinase (Ser675), and Akt (Ser552) phosphorylate β‐catenin and enhance its transcriptional activity 58–61 .…”

A deep tabular data learning model predicting cisplatin sensitivity identifies BCL2L1 dependency in cancer

“…To illustrate, cisplatin-resistant non-small cell lung cancer (NSCLC) cell line showed upregulation of β-catenin due to phosphorylation-dependent inhibition of GSK3β [42] , and cisplatin-resistant hepatocellular carcinoma cells exhibited nuclear accumulation of GSK3β [43] . GSK3β is an essential component of the destruction complex that maintains a β-catenin cellular level by inducing phosphorylation-dependent degradation [44] . Stabilization of β-catenin, caused by phosphorylation-dependent inhibition of GSK3β, facilitates nuclear translocation and transcription of WNT response genes.…”

Circular RNAs regulate parental gene expression: A new direction for molecular oncology research

“…These results suggested that the FBXW7-185aa protein encoded by circ-FBXW7 could inhibit ubiquitination of the parent gene protein by competitively binding USP28, thus downregulating c-MYC expression and inhibiting the occurrence and development of breast cancer. The abnormal activation of Wnt/β-catenin signaling pathways was closely associated with increased prevalence, malignant progression, development of poor prognosis, and even increased cancer-related mortality ( 45 ). Liang et al.…”