| Structural highlights
Disease
CTNB1_HUMAN Defects in CTNNB1 are associated with colorectal cancer (CRC) [MIM:114500. Note=Activating mutations in CTNNB1 have oncogenic activity resulting in tumor development. Somatic mutations are found in various tumor types, including colon cancers, ovarian and prostate carcinomas, hepatoblastoma (HB), hepatocellular carcinoma (HCC). HBs are malignant embryonal tumors mainly affecting young children in the first three years of life. Defects in CTNNB1 are a cause of pilomatrixoma (PTR) [MIM:132600; a common benign skin tumor.[1] [2] [3] Defects in CTNNB1 are a cause of medulloblastoma (MDB) [MIM:155255. MDB is a malignant, invasive embryonal tumor of the cerebellum with a preferential manifestation in children.[4] [5] Defects in CTNNB1 are a cause of susceptibility to ovarian cancer (OC) [MIM:167000. Ovarian cancer common malignancy originating from ovarian tissue. Although many histologic types of ovarian neoplasms have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. Note=A chromosomal aberration involving CTNNB1 is found in salivary gland pleiomorphic adenomas, the most common benign epithelial tumors of the salivary gland. Translocation t(3;8)(p21;q12) with PLAG1. Defects in CTNNB1 may be a cause of mesothelioma malignant (MESOM) [MIM:156240. An aggressive neoplasm of the serosal lining of the chest. It appears as broad sheets of cells, with some regions containing spindle-shaped, sarcoma-like cells and other regions showing adenomatous patterns. Pleural mesotheliomas have been linked to exposure to asbestos.[6]
Function
CTNB1_HUMAN Key downstream component of the canonical Wnt signaling pathway. In the absence of Wnt, forms a complex with AXIN1, AXIN2, APC, CSNK1A1 and GSK3B that promotes phosphorylation on N-terminal Ser and Thr residues and ubiquitination of CTNNB1 via BTRC and its subsequent degradation by the proteasome. In the presence of Wnt ligand, CTNNB1 is not ubiquitinated and accumulates in the nucleus, where it acts as a coactivator for transcription factors of the TCF/LEF family, leading to activate Wnt responsive genes. Involved in the regulation of cell adhesion. Acts as a negative regulator of centrosome cohesion. Involved in the CDK2/PTPN6/CTNNB1/CEACAM1 pathway of insulin internalization. Blocks anoikis of malignant kidney and intestinal epithelial cells and promotes their anchorage-independent growth by down-regulating DAPK2.[7] [8] [9] [10]
Publication Abstract from PubMed
The alpha-helix is one of the most common protein surface recognition motifs found in nature, and its unique amide-cloaking properties also enable alpha-helical polypeptide motifs to exist in membranes. Together, these properties have inspired the development of alpha-helically constrained (Helicon) therapeutics that can enter cells and bind targets that have been considered "undruggable", such as protein-protein interactions. To date, no general method for discovering alpha-helical binders to proteins has been reported, limiting Helicon drug discovery to only those proteins with previously characterized alpha-helix recognition sites, and restricting the starting chemical matter to those known alpha-helical binders. Here, we report a general and rapid screening method to empirically map the alpha-helix binding sites on a broad range of target proteins in parallel using large, unbiased Helicon phage display libraries and next-generation sequencing. We apply this method to screen six structurally diverse protein domains, only one of which had been previously reported to bind isolated alpha-helical peptides, discovering 20 families that collectively comprise several hundred individual Helicons. Analysis of 14 X-ray cocrystal structures reveals at least nine distinct alpha-helix recognition sites across these six proteins, and biochemical and biophysical studies show that these Helicons can block protein-protein interactions, inhibit enzymatic activity, induce conformational rearrangements, and cause protein dimerization. We anticipate that this method will prove broadly useful for the study of protein recognition and for the development of both biochemical tools and therapeutics for traditionally challenging protein targets.
De novo mapping of alpha-helix recognition sites on protein surfaces using unbiased libraries.,Li K, Tokareva OS, Thomson TM, Wahl SCT, Travaline TL, Ramirez JD, Choudary SK, Agarwal S, Walkup WG 4th, Olsen TJ, Brennan MJ, Verdine GL, McGee JH Proc Natl Acad Sci U S A. 2022 Dec 27;119(52):e2210435119. doi: , 10.1073/pnas.2210435119. Epub 2022 Dec 19. PMID:36534810[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Moreno-Bueno G, Gamallo C, Perez-Gallego L, Contreras F, Palacios J. beta-catenin expression in pilomatrixomas. Relationship with beta-catenin gene mutations and comparison with beta-catenin expression in normal hair follicles. Br J Dermatol. 2001 Oct;145(4):576-81. PMID:11703283
- ↑ van Noort M, van de Wetering M, Clevers H. Identification of two novel regulated serines in the N terminus of beta-catenin. Exp Cell Res. 2002 Jun 10;276(2):264-72. PMID:12027456 doi:10.1006/excr.2002.5520
- ↑ Chan EF, Gat U, McNiff JM, Fuchs E. A common human skin tumour is caused by activating mutations in beta-catenin. Nat Genet. 1999 Apr;21(4):410-3. PMID:10192393 doi:10.1038/7747
- ↑ van Noort M, van de Wetering M, Clevers H. Identification of two novel regulated serines in the N terminus of beta-catenin. Exp Cell Res. 2002 Jun 10;276(2):264-72. PMID:12027456 doi:10.1006/excr.2002.5520
- ↑ Huang H, Mahler-Araujo BM, Sankila A, Chimelli L, Yonekawa Y, Kleihues P, Ohgaki H. APC mutations in sporadic medulloblastomas. Am J Pathol. 2000 Feb;156(2):433-7. PMID:10666372
- ↑ Shigemitsu K, Sekido Y, Usami N, Mori S, Sato M, Horio Y, Hasegawa Y, Bader SA, Gazdar AF, Minna JD, Hida T, Yoshioka H, Imaizumi M, Ueda Y, Takahashi M, Shimokata K. Genetic alteration of the beta-catenin gene (CTNNB1) in human lung cancer and malignant mesothelioma and identification of a new 3p21.3 homozygous deletion. Oncogene. 2001 Jul 12;20(31):4249-57. PMID:11464291 doi:10.1038/sj.onc.1204557
- ↑ Lillehoj EP, Lu W, Kiser T, Goldblum SE, Kim KC. MUC1 inhibits cell proliferation by a beta-catenin-dependent mechanism. Biochim Biophys Acta. 2007 Jul;1773(7):1028-38. Epub 2007 Apr 22. PMID:17524503 doi:S0167-4889(07)00092-4
- ↑ Bahmanyar S, Kaplan DD, Deluca JG, Giddings TH Jr, O'Toole ET, Winey M, Salmon ED, Casey PJ, Nelson WJ, Barth AI. beta-Catenin is a Nek2 substrate involved in centrosome separation. Genes Dev. 2008 Jan 1;22(1):91-105. Epub 2007 Dec 17. PMID:18086858 doi:10.1101/gad.1596308
- ↑ Li H, Ray G, Yoo BH, Erdogan M, Rosen KV. Down-regulation of death-associated protein kinase-2 is required for beta-catenin-induced anoikis resistance of malignant epithelial cells. J Biol Chem. 2009 Jan 23;284(4):2012-22. doi: 10.1074/jbc.M805612200. Epub 2008, Oct 27. PMID:18957423 doi:10.1074/jbc.M805612200
- ↑ Fiset A, Xu E, Bergeron S, Marette A, Pelletier G, Siminovitch KA, Olivier M, Beauchemin N, Faure RL. Compartmentalized CDK2 is connected with SHP-1 and beta-catenin and regulates insulin internalization. Cell Signal. 2011 May;23(5):911-9. doi: 10.1016/j.cellsig.2011.01.019. Epub 2011 , Jan 22. PMID:21262353 doi:10.1016/j.cellsig.2011.01.019
- ↑ Li K, Tokareva OS, Thomson TM, Wahl SCT, Travaline TL, Ramirez JD, Choudary SK, Agarwal S, Walkup WG 4th, Olsen TJ, Brennan MJ, Verdine GL, McGee JH. De novo mapping of alpha-helix recognition sites on protein surfaces using unbiased libraries. Proc Natl Acad Sci U S A. 2022 Dec 27;119(52):e2210435119. doi: , 10.1073/pnas.2210435119. Epub 2022 Dec 19. PMID:36534810 doi:http://dx.doi.org/10.1073/pnas.2210435119
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