The role of the Wnt signalling pathway in colorectal tumorigenesis

2005 ◽  
Vol 33 (4) ◽  
pp. 672-675 ◽  
Author(s):  
J. Behrens
Keyword(s):  
Wnt Pathway ◽  
Genetic Alterations ◽  
Wnt Signalling ◽  
Tumour Suppressor ◽  
Tumour Suppressor Genes ◽  
Adenomatous Polyposis ◽  
Polyposis Coli ◽  
Colorectal Tumorigenesis ◽  
Constitutive Activation

Colorectal cancer (CRC) is the second largest cause of cancer-related deaths in Western countries. CRC arises from the colorectal epithelium as a result of the accumulation of genetic alterations in defined oncogenes and tumour suppressor genes. Mutations in the tumour suppressor APC (adenomatous polyposis coli) genes occur early in the development of CRC and lead to the stabilization of the Wnt pathway component β-catenin and to the constitutive activation of Wnt signalling. Stabilizing mutations of β-catenin can also lead to its accumulation, qualifying β-catenin as a proto-oncogene. Here I will summarize the biochemical interactions occurring in Wnt signalling and describe how alterations in Wnt pathway components lead to CRC.

scholarly journals The Adenomatous polyposis coli tumour suppressor is essential for Axin complex assembly and function and opposes Axin's interaction with Dishevelled

Open Biology ◽  
2011 ◽  
Vol 1 (3) ◽  
pp. 110013 ◽  
Author(s):  
Carolina Mendoza-Topaz ◽  
Juliusz Mieszczanek ◽  
Mariann Bienz
Keyword(s):  
Adenomatous Polyposis Coli ◽  
Self Assembly ◽  
Wnt Signalling ◽  
Tumour Suppressor ◽  
Adenomatous Polyposis ◽  
Polyposis Coli ◽  
Protein Assemblies ◽  
Membrane Recruitment ◽  
And Function

Most cases of colorectal cancer are linked to mutational inactivation of the Adenomatous polyposis coli (APC) tumour suppressor. APC downregulates Wnt signalling by enabling Axin to promote the degradation of the Wnt signalling effector β-catenin (Armadillo in flies). This depends on Axin's DIX domain whose polymerization allows it to form dynamic protein assemblies (‘degradasomes’). Axin is inactivated upon Wnt signalling, by heteropolymerization with the DIX domain of Dishevelled, which recruits it into membrane-associated ‘signalosomes’. How APC promotes Axin's function is unclear, especially as it has been reported that APC's function can be bypassed by overexpression of Axin. Examining apc null mutant Drosophila tissues, we discovered that APC is required for Axin degradasome assembly, itself essential for Armadillo downregulation. Degradasome assembly is also attenuated in APC mutant cancer cells. Notably, Axin becomes prone to Dishevelled-dependent plasma membrane recruitment in the absence of APC, indicating a crucial role of APC in opposing the interaction of Axin with Dishevelled. Indeed, co-expression experiments reveal that APC displaces Dishevelled from Axin assemblies, promoting degradasome over signalosome formation in the absence of Wnts. APC thus empowers Axin to function in two ways—by enabling its DIX-dependent self-assembly, and by opposing its DIX-dependent copolymerization with Dishevelled and consequent inactivation.

scholarly journals Oncogenic Mutants of RON and MET Receptor Tyrosine Kinases Cause Activation of the β-Catenin Pathway

2001 ◽  
Vol 21 (17) ◽  
pp. 5857-5868 ◽  
Author(s):  
Alla Danilkovitch-Miagkova ◽  
Alexei Miagkov ◽  
Alison Skeel ◽  
Noboru Nakaigawa ◽  
Berton Zbar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Cell Transformation ◽  
Transcriptional Factor ◽  
Adenomatous Polyposis ◽  
Polyposis Coli ◽  
Met Receptor ◽  
Constitutive Activation ◽  
Oncogenic Protein

ABSTRACT β-Catenin is an oncogenic protein involved in regulation of cell-cell adhesion and gene expression. Accumulation of cellular β-catenin occurs in many types of human cancers. Four mechanisms are known to cause increases in β-catenin: mutations of β-catenin, adenomatous polyposis coli, or axin genes and activation of Wnt signaling. We report a new cause of β-catenin accumulation involving oncogenic mutants of RON and MET receptor tyrosine kinases (RTKs). Cells transfected with oncogenic RON or MET were characterized by β-catenin tyrosine phosphorylation and accumulation; constitutive activation of a Tcf transcriptional factor; and increased levels of β-catenin/Tcf target oncogene proteins c-mycand cyclin D1. Interference with the β-catenin pathway reduced the transforming potential of mutated RON and MET. Activation of β-catenin by oncogenic RON and MET constitutes a new pathway, which might lead to cell transformation by these and other mutant growth factor RTKs.

scholarly journals YAP–IL-6ST autoregulatory loop activated on APC loss controls colonic tumorigenesis

2017 ◽  
Vol 114 (7) ◽  
pp. 1643-1648 ◽  
Author(s):  
Koji Taniguchi ◽  
Toshiro Moroishi ◽  
Petrus R. de Jong ◽  
Michal Krawczyk ◽  
Britta Moyo Grebbin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Src Family Kinases ◽  
Serine Phosphorylation ◽  
Signal Transducer ◽  
Adenomatous Polyposis ◽  
Colorectal Tumors ◽  
Polyposis Coli ◽  
Human Colorectal Cancer ◽  
Colorectal Tumorigenesis ◽  
Activating Mutations

Loss of tumor suppressor adenomatous polyposis coli (APC) activates β-catenin to initiate colorectal tumorigenesis. However, β-catenin (CTNNB1) activating mutations rarely occur in human colorectal cancer (CRC). We found that APC loss also results in up-regulation of IL-6 signal transducer (IL-6ST/gp130), thereby activating Src family kinases (SFKs), YAP, and STAT3, which are simultaneously up-regulated in the majority of human CRC. Although, initial YAP activation, which stimulates IL6ST gene transcription, may be caused by reduced serine phosphorylation, sustained YAP activation depends on tyrosine phosphorylation by SFKs, whose inhibition, along with STAT3-activating JAK kinases, causes regression of established colorectal tumors. These results explain why APC loss is a more potent initiating event than the mere activation of CTNNB1.

Role of ESCRT component HD-PTP/PTPN23 in cancer

2017 ◽  
Vol 45 (3) ◽  
pp. 845-854 ◽  
Author(s):  
Marie-Claude Gingras ◽  
Jalal M. Kazan ◽  
Arnim Pause
Keyword(s):  
Plasma Membrane ◽  
Cancer Susceptibility ◽  
Tumour Suppressor ◽  
Tumour Suppressor Genes ◽  
Surface Receptors ◽  
Endosomal Sorting ◽  
Bona Fide

Sustained cellular signalling originated from the receptors located at the plasma membrane is widely associated with cancer susceptibility. Endosomal sorting and degradation of the cell surface receptors is therefore crucial to preventing chronic downstream signalling and tumorigenesis. Since the Endosomal Sorting Complexes Required for Transport (ESCRT) controls these processes, ESCRT components were proposed to act as tumour suppressor genes. However, the bona fide role of ESCRT components in tumorigenesis has not been clearly demonstrated. The ESCRT member HD-PTP/PTPN23 was recently identified as a novel haplo-insufficient tumour suppressor in vitro and in vivo, in mice and humans. In this mini-review, we outline the role of the ESCRT components in cancer and summarize the functions of HD-PTP/PTPN23 in tumorigenesis.

Truncated adenomatous polyposis coli (APC) tumour suppressor protein can undergo tyrosine phosphorylation

2000 ◽  
Vol 36 (4) ◽  
pp. 525-532 ◽  
Author(s):  
A.L. Norris ◽  
P.M. Clissold ◽  
J.M. Askham ◽  
E.E. Morrison ◽  
P. Moncur ◽  
...  
Keyword(s):  
Tyrosine Phosphorylation ◽  
Adenomatous Polyposis Coli ◽  
Tumour Suppressor ◽  
Adenomatous Polyposis ◽  
Polyposis Coli ◽  
Tumour Suppressor Protein
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