3sla | pdb_00003sla
X-ray structure of first four repeats of human beta-catenin
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 PubMedWnt/beta-catenin signalling controls development and tissue homeostasis. Moreover, activated beta-catenin can be oncogenic and, notably, drives colorectal cancer. Inhibiting oncogenic beta-catenin has proven a formidable challenge. Here we design a screen for small-molecule inhibitors of beta-catenin's binding to its cofactor BCL9, and discover five related natural compounds, including carnosic acid from rosemary, which attenuates transcriptional beta-catenin outputs in colorectal cancer cells. Evidence from NMR and analytical ultracentrifugation demonstrates that the carnosic acid response requires an intrinsically labile alpha-helix (H1) amino-terminally abutting the BCL9-binding site in beta-catenin. Similarly, in colorectal cancer cells with hyperactive beta-catenin signalling, carnosic acid targets predominantly the transcriptionally active ('oncogenic') form of beta-catenin for proteasomal degradation in an H1-dependent manner. Hence, H1 is an 'Achilles' Heel' of beta-catenin, which can be exploited for destabilization of oncogenic beta-catenin by small molecules, providing proof-of-principle for a new strategy for developing direct inhibitors of oncogenic beta-catenin. An intrinsically labile alpha-helix abutting the BCL9-binding site of beta-catenin is required for its inhibition by carnosic acid.,de la Roche M, Rutherford TJ, Gupta D, Veprintsev DB, Saxty B, Freund SM, Bienz M Nat Commun. 2012 Feb 21;3:680. doi: 10.1038/ncomms1680. PMID:22353711[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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