The WNT Signaling Pathway in Development and Disease

Logan, Cheryl A.; Nusse, Roel

doi:10.1146/annurev.cellbio.20.010403.113126

Cited by 4,791 publications

(4,330 citation statements)

References 197 publications

(151 reference statements)

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“…Secreted Wnt proteins can act as morphogens and are implicated in many processes during embryonic development and adult tissue homeostasis (Logan & Nusse, 2004). In addition, de‐regulation of the Wnt pathway has been implicated in the onset and progression of tumorigenesis (Clevers, 2006).…”

Section: Discussionmentioning

confidence: 99%

ERAD‐dependent control of the Wnt secretory factor Evi

et al. 2018

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Active regulation of protein abundance is an essential strategy to modulate cellular signaling pathways. Within the Wnt signaling cascade, regulated degradation of β‐catenin by the ubiquitin‐proteasome system (UPS) affects the outcome of canonical Wnt signaling. Here, we found that abundance of the Wnt cargo receptor Evi (Wls/GPR177), which is required for Wnt protein secretion, is also regulated by the UPS through endoplasmic reticulum (ER)‐associated degradation (ERAD). In the absence of Wnt ligands, Evi is ubiquitinated and targeted for ERAD in a VCP‐dependent manner. Ubiquitination of Evi involves the E2‐conjugating enzyme UBE2J2 and the E3‐ligase CGRRF1. Furthermore, we show that a triaging complex of Porcn and VCP determines whether Evi enters the secretory or the ERAD pathway. In this way, ERAD‐dependent control of Evi availability impacts the scale of Wnt protein secretion by adjusting the amount of Evi to meet the requirement of Wnt protein export. As Wnt and Evi protein levels are often dysregulated in cancer, targeting regulatory ERAD components might be a useful approach for therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

ERAD‐dependent control of the Wnt secretory factor Evi

et al. 2018

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“…Briefly, the Wnt signaling pathway is an evolutionarily conserved pathway across kingdom Animalia and plays a crucial role in pattern formation during embryogenesis 9. The Wnt signal transduction pathway plays a crucial role in organ formation in embryonic development, cell proliferation, polarity, migration, and differentiation 10. Thus, deregulated Wnt signaling is associated with many human diseases 11.…”

Section: Introductionmentioning

confidence: 99%

Atherosclerotic Calcification: Wnt Is the Hint

Albanese

Khan

Barratt

et al. 2018

JAHA

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“…Similar to the Shh pathway, the wingless-Int (Wnt) and bone morphogenetic protein/transforming growth factor-b (BMP/TGF-b) pathways play central developmental roles that are conserved from the fruitfly to human (Chen and Meng, 2004;Logan and Nusse, 2004). Mutations and deregulation of the Wnt pathway are the characteristic features of many human cancers, most notably in intestinal malignancies (Gregorieff and Clevers, 2005).…”

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confidence: 99%

RUNX3 protein is overexpressed in human basal cell carcinomas

et al. 2006

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Basal cell carcinomas (BCC), which are the most common form of skin malignancy, are invariably associated with the deregulation of the Sonic Hedgehog (Shh) signalling pathway. As such, BCC represent a unique model for the study of interactions of the Shh pathway with other genes and pathways. We constructed a tissue microarray (TMA) of 75 paired BCC and normal skin and analysed the expression of b-catenin and RUNX3, nuclear effectors of the wingless-Int (Wnt) and bone morphogenetic protein/ transforming growth factor-b pathways, respectively. In line with previous reports, we observed varying subcellular expression pattern of b-catenin in BCC, with 31 cases (41%) showing nuclear accumulation. In contrast, all the BCC cases tested by the TMA showed RUNX3 protein uniformly overexpressed in the nuclei of the cancer cells. Analysis by Western blotting and DNA sequencing indicates that the overexpressed protein is normal and full-length, containing no mutation in the coding region, implicating RUNX3 as an oncogene in certain human cancers. Our results indicate that although the deregulation of Wnt signalling could contribute to the pathogenesis of a subset of BCC, RUNX3 appears to be a universal downstream mediator of a constitutively active Shh pathway in BCC.

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The WNT Signaling Pathway in Development and Disease

Cited by 4,791 publications

References 197 publications

ERAD‐dependent control of the Wnt secretory factor Evi

ERAD‐dependent control of the Wnt secretory factor Evi

Atherosclerotic Calcification: Wnt Is the Hint

RUNX3 protein is overexpressed in human basal cell carcinomas

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