Βeta-catenin N-terminal domain: An enigmatic region prone to cancer causing mutations

Dar, Mohd Saleem; Paramjeet, Singh; Mir, Riyaz Ahmad; Dar, Mohd Jamal

doi:10.1016/j.mrrev.2017.06.001

Cited by 21 publications

(12 citation statements)

References 106 publications

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“…Akyol et al (2019) defined an immunohistochemical algorithm to dissect Wnt pathway alterations in formalin-fixed and paraffin-embedded neoplastic tissues and found all six colon adenomas of the 126 total adenomas studied for the altered/ mutant b-catenin staining pattern had presumptively pathogenic point mutations or deletions in CTNNB1. The N-terminus of b-catenin, with contains conserved phosphorylated threonine/ serine amino acid residues, is the most frequent location of cancer-related CTNNB1 mutations (Dar et al, 2017). The level of free b-catenin in the cytoplasmic pool is regulated by ubiquitination and proteasomal degradation (Akyol et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Analysis of the Clinicopathologic Characteristics of Lung Adenocarcinoma With CTNNB1 Mutation

Zhou

Shao

et al. 2020

Front. Genet.

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Introduction: Lung adenocarcinoma with CTNNB1 mutation is relatively uncommon, and its clinicopathologic characteristics, disease course, and prognosis have not been well-studied.Methods: A total of 564 lung adenocarcinoma patients were enrolled in this study. The relationship between CTTNB1 mutational status and clinicopathologic parameters, the rates of relapse-free survival (RFS) and overall survival (OS), and the mutational status of other genes commonly mutated in lung adenocarcinoma were analyzed.Results: Of 564 lung adenocarcinoma patients, 30 (5.3%) harbored CTNNB1 mutations. Univariate analyses revealed that gender, smoking history, pleural invasion, and histological subtype were all significant predictors of RFS and OS. Pleural invasion and histological subtype remained significant predictors of RFS and OS in a multivariate analysis. There were no significant differences in RFS (p = 0.504) or OS (p = 0.054) between lung adenocarcinoma patients with CTNNB1 mutation and those without CTNNB1 mutation. However, patients with CTNNB1 mutation tended to have a worse OS.Conclusions: Female patients and nonsmokers are likely to harbor CTNNB1 mutation and primary lung adenocarcinoma with mutated CTNNB1 has a poor prognosis.

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Section: Introductionmentioning

confidence: 99%

Analysis of the Clinicopathologic Characteristics of Lung Adenocarcinoma With CTNNB1 Mutation

Zhou

Shao

et al. 2020

Front. Genet.

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“…The CTNNB1 cancer-associated mutations mostly affect the N-terminus of β-catenin, which contains conserved serine/threonine amino acid residues that are phosphorylated. The levels of the cytoplasmic pool of free β-catenin are tightly regulated by ubiquitination and proteasomal degradation [5,6]. In normal physiological and pathological conditions, β-catenin's function in the Wnt signaling pathway is determined by its levels and subcellular localization.…”

Section: Introductionmentioning

confidence: 99%

An immunohistochemical approach to detect oncogenic CTNNB1 mutations in primary neoplastic tissues

Akyol

Güner

Özşeker

et al. 2019

Laboratory Investigation

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The Wnt/β-catenin signaling pathway is dysregulated in different types of neoplasms including colorectal cancer (CRC). Aberrant activation of this signaling pathway is a key early event in the development of colorectal neoplasms, and is mainly caused by loss of function mutations in Adenomatous Polyposis Coli (APC), and less frequently by β-catenin stabilization mutations via missense or interstitial genomic deletions in CTNNB1. In this study, we have defined an immunohistochemical algorithm to dissect Wnt pathway alterations in formalin-fixed and paraffin-embedded neoplastic tissues. Basically, consecutive sections of tumor specimens were stained by immunohistochemistry with two different monoclonal antibodies against β-catenin: one (anti-active β-catenin antibody) recognizes hypo-phosphorylated β-catenin and the other recognizes the total pool of β-catenin. We validated the strategy in the HCT116 CRC cell line which has an in-frame deletion of β-catenin serine 45, and then studied human tumor microarrays containing colon adenomas, CRCs, solid pseudopapillary neoplasms of the pancreas as well as the whole tissue sections of CRCs, desmoid fibromatosis, and pilomatrixoma of the skin. In some tumors, we found strong β-catenin cytoplasmic and/or nuclear staining with the total β-catenin antibody but no staining with the anti-active β-catenin antibody. This was inferred to be an altered/mutant β-catenin staining pattern. All six colon adenomas of the 126 total adenomas studied for the altered/mutant β-catenin staining pattern had presumptively pathogenic point mutations or deletions in CTNNB1. Four of 10 CRCs with the alterated/mutant β-catenin staining pattern studied in depth, from 181 total CRCs from tissue microarray, had pathogenic CTNNB1 mutations. The frequencies of CTNNB1 alterations in non-colonic tumors with altered/mutant β-catenin staining ranged between 46 and 100%. Our results demonstrate that the immunohistochemical approach described here can detect oncogenic forms of β-catenin in primary tissue samples and can also highlight other tumors with presumptive novel defects activating the Wnt/β-catenin pathway.

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“…Indeed, biophysical simulations suggest that cancer-associated missense mutations in the AS of the tumor suppressors ASK1 and DAPK2 reduce activity of these genes, while they increase the activating interactions between that the oncogenes eIF4E and eIF4G1. It is important to note that missense mutations, as well as truncations as a result of gene fusion, in signal-integrating ASs can also affect other aspects of protein regulation than allostery such as cell localization or protein half-life 74,94 , which in turn can promote cancer development. Besides providing leads for the potential molecular effects in oncogenes or tumor suppressors, our analysis demonstrates that missense mutations in allosteric switches are associated with specific transcriptional signatures of cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Consistent with the prediction of the AS, structural and binding studies have revealed that the N-terminal tail (and C-terminal tail) of b-catenin transiently interacts with other parts of the protein and, thereby, modulates interactions with binding partners [70][71][72] . However, the N-terminal tail also harbors multiple phosphorylation sites that are key to the regulation of b-catenin's ubiquitin-mediated degradation and subcellular localization, and the oncogenic potential of missense mutations located in this N-terminal tail has been explained mainly by changes in protein stability and localization 73,74 .…”

Section: Significantly Mutated Inhibitory Allosteric Switches Are Assmentioning

confidence: 99%

Widespread alteration of protein autoinhibition in human cancers

Gsponer

Jha

Bui

et al. 2018

Preprint

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Autoinhibition is a prevalent allosteric regulatory mechanism in signaling proteins as it prevents spurious pathway activation and primes for signal propagation only under appropriate inputs. Altered functioning of inhibitory allosteric switches underlies the tumorigenic potential of numerous cancer drivers. However, whether protein autoinhibition is altered generically in cancer cells remains elusive. Here, we reveal that cancer-associated missense mutations and fusion breakpoints are found with significant enrichment within inhibitory allosteric switches across all cancer types, which in the case of the fusion breakpoints is specific to cancer and not present in other diseases. Recurrently disrupted or mutated allosteric switches identify established and new cancer drivers. Cancer-specific mutations in allosteric switches are associated with distinct changes in signaling, and suggest molecular mechanisms for altered protein regulation, which in the case of ASK1, DAPK2 and EIF4G1 were supported by biophysical simulations. Our results demonstrate that autoinhibition-modulating genetic alterations are positively selected for by cancer cells, and that their study provides valuable insights into molecular mechanisms of cancer misregulation.

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Βeta-catenin N-terminal domain: An enigmatic region prone to cancer causing mutations

Cited by 21 publications

References 106 publications

Analysis of the Clinicopathologic Characteristics of Lung Adenocarcinoma With CTNNB1 Mutation

Analysis of the Clinicopathologic Characteristics of Lung Adenocarcinoma With CTNNB1 Mutation

An immunohistochemical approach to detect oncogenic CTNNB1 mutations in primary neoplastic tissues

Widespread alteration of protein autoinhibition in human cancers

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