| Structural highlights
Disease
MUC1_HUMAN Note=MUC1/CA 15-3 is used as a serological clinical marker of breast cancer to monitor response to breast cancer treatment and disease recurrence (PubMed:20816948). Decreased levels over time may be indicative of a positive response to treatment. Conversely, increased levels may indicate disease progression. At an early stage disease, only 21% of patients exhibit high MUC1/CA 15-3 levels, that is why CA 15-3 is not a useful screening test. Most antibodies target the highly immunodominant core peptide domain of 20 amino acid (APDTRPAPGSTAPPAHGVTS) tandem repeats. Some antibodies recognize glycosylated epitopes.
Function
MUC1_HUMAN The alpha subunit has cell adhesive properties. Can act both as an adhesion and an anti-adhesion protein. May provide a protective layer on epithelial cells against bacterial and enzyme attack.[1] [2] [3] [4] [5] [6] [7] [8] [9] The beta subunit contains a C-terminal domain which is involved in cell signaling, through phosphorylations and protein-protein interactions. Modulates signaling in ERK, SRC and NF-kappa-B pathways. In activated T-cells, influences directly or indirectly the Ras/MAPK pathway. Promotes tumor progression. Regulates TP53-mediated transcription and determines cell fate in the genotoxic stress response. Binds, together with KLF4, the PE21 promoter element of TP53 and represses TP53 activity.[10] [11] [12] [13] [14] [15] [16] [17] [18]
Publication Abstract from PubMed
The tumor-associated carbohydrate Tn antigens include two variants, alphaGalNAc- O-Thr and alphaGalNAc- O-Ser. In solution, they exhibit dissimilar shapes and dynamics and bind differently to the same protein receptor. Here, we demonstrate experimentally and theoretically that their conformational preferences in the gas phase are highly similar, revealing the essential role of water. We propose that water molecules prompt the rotation around the glycosidic linkage in the threonine derivative, shielding its hydrophobic methyl group and allowing an optimal solvation of the polar region of the antigen. The unusual arrangement of alphaGalNAc- O-Thr features a water molecule bound into a "pocket" between the sugar and the threonine. This mechanism is supported by trapping, for the first time, such localized water in the crystal structures of an antibody bound to two glycopeptides that comprise fluorinated Tn antigens in their structure. According to several reported X-ray structures, installing oxygenated amino acids in specific regions of the receptor capable of displacing the bridging water molecule to the bulk-solvent may facilitate the molecular recognition of the Tn antigen with threonine. Overall, our data also explain how water fine-tunes the 3D structure features of similar molecules, which in turn are behind their distinct biological activities.
Water Sculpts the Distinctive Shapes and Dynamics of the Tumor-Associated Carbohydrate Tn Antigens: Implications for Their Molecular Recognition.,Bermejo IA, Usabiaga I, Companon I, Castro-Lopez J, Insausti A, Fernandez JA, Avenoza A, Busto JH, Jimenez-Barbero J, Asensio JL, Peregrina JM, Jimenez-Oses G, Hurtado-Guerrero R, Cocinero EJ, Corzana F J Am Chem Soc. 2018 Aug 8;140(31):9952-9960. doi: 10.1021/jacs.8b04801. Epub 2018 , Jul 30. PMID:30004703[19]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Yamamoto M, Bharti A, Li Y, Kufe D. Interaction of the DF3/MUC1 breast carcinoma-associated antigen and beta-catenin in cell adhesion. J Biol Chem. 1997 May 9;272(19):12492-4. PMID:9139698
- ↑ Ren J, Li Y, Kufe D. Protein kinase C delta regulates function of the DF3/MUC1 carcinoma antigen in beta-catenin signaling. J Biol Chem. 2002 May 17;277(20):17616-22. Epub 2002 Mar 4. PMID:11877440 doi:10.1074/jbc.M200436200
- ↑ Huang L, Ren J, Chen D, Li Y, Kharbanda S, Kufe D. MUC1 cytoplasmic domain coactivates Wnt target gene transcription and confers transformation. Cancer Biol Ther. 2003 Nov-Dec;2(6):702-6. PMID:14688481
- ↑ Wei X, Xu H, Kufe D. Human MUC1 oncoprotein regulates p53-responsive gene transcription in the genotoxic stress response. Cancer Cell. 2005 Feb;7(2):167-78. PMID:15710329 doi:10.1016/j.ccr.2005.01.008
- ↑ Huang L, Chen D, Liu D, Yin L, Kharbanda S, Kufe D. MUC1 oncoprotein blocks glycogen synthase kinase 3beta-mediated phosphorylation and degradation of beta-catenin. Cancer Res. 2005 Nov 15;65(22):10413-22. PMID:16288032 doi:65/22/10413
- ↑ Mukherjee P, Tinder TL, Basu GD, Gendler SJ. MUC1 (CD227) interacts with lck tyrosine kinase in Jurkat lymphoma cells and normal T cells. J Leukoc Biol. 2005 Jan;77(1):90-9. Epub 2004 Oct 28. PMID:15513966 doi:jlb.0604333
- ↑ 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
- ↑ Wei X, Xu H, Kufe D. Human mucin 1 oncoprotein represses transcription of the p53 tumor suppressor gene. Cancer Res. 2007 Feb 15;67(4):1853-8. PMID:17308127 doi:67/4/1853
- ↑ Pochampalli MR, el Bejjani RM, Schroeder JA. MUC1 is a novel regulator of ErbB1 receptor trafficking. Oncogene. 2007 Mar 15;26(12):1693-701. Epub 2006 Sep 18. PMID:16983337 doi:1209976
- ↑ Yamamoto M, Bharti A, Li Y, Kufe D. Interaction of the DF3/MUC1 breast carcinoma-associated antigen and beta-catenin in cell adhesion. J Biol Chem. 1997 May 9;272(19):12492-4. PMID:9139698
- ↑ Ren J, Li Y, Kufe D. Protein kinase C delta regulates function of the DF3/MUC1 carcinoma antigen in beta-catenin signaling. J Biol Chem. 2002 May 17;277(20):17616-22. Epub 2002 Mar 4. PMID:11877440 doi:10.1074/jbc.M200436200
- ↑ Huang L, Ren J, Chen D, Li Y, Kharbanda S, Kufe D. MUC1 cytoplasmic domain coactivates Wnt target gene transcription and confers transformation. Cancer Biol Ther. 2003 Nov-Dec;2(6):702-6. PMID:14688481
- ↑ Wei X, Xu H, Kufe D. Human MUC1 oncoprotein regulates p53-responsive gene transcription in the genotoxic stress response. Cancer Cell. 2005 Feb;7(2):167-78. PMID:15710329 doi:10.1016/j.ccr.2005.01.008
- ↑ Huang L, Chen D, Liu D, Yin L, Kharbanda S, Kufe D. MUC1 oncoprotein blocks glycogen synthase kinase 3beta-mediated phosphorylation and degradation of beta-catenin. Cancer Res. 2005 Nov 15;65(22):10413-22. PMID:16288032 doi:65/22/10413
- ↑ Mukherjee P, Tinder TL, Basu GD, Gendler SJ. MUC1 (CD227) interacts with lck tyrosine kinase in Jurkat lymphoma cells and normal T cells. J Leukoc Biol. 2005 Jan;77(1):90-9. Epub 2004 Oct 28. PMID:15513966 doi:jlb.0604333
- ↑ 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
- ↑ Wei X, Xu H, Kufe D. Human mucin 1 oncoprotein represses transcription of the p53 tumor suppressor gene. Cancer Res. 2007 Feb 15;67(4):1853-8. PMID:17308127 doi:67/4/1853
- ↑ Pochampalli MR, el Bejjani RM, Schroeder JA. MUC1 is a novel regulator of ErbB1 receptor trafficking. Oncogene. 2007 Mar 15;26(12):1693-701. Epub 2006 Sep 18. PMID:16983337 doi:1209976
- ↑ Bermejo IA, Usabiaga I, Compañón I, Castro-López J, Insausti A, Fernández JA, Avenoza A, Busto JH, Jiménez-Barbero J, Asensio JL, Peregrina JM, Jiménez-Osés G, Hurtado-Guerrero R, Cocinero EJ, Corzana F. Water Sculpts the Distinctive Shapes and Dynamics of the Tumor-Associated Carbohydrate Tn Antigens: Implications for Their Molecular Recognition. J Am Chem Soc. 2018 Aug 8;140(31):9952-9960. PMID:30004703 doi:10.1021/jacs.8b04801
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