Bibliographic Details
| Title: |
Functional Characterization of POFUT1 Variants Associated with Colorectal Cancer. |
| Authors: |
Deschuyter, Marlène1 (AUTHOR) marlene.deschuyter@unilim.fr, Pennarubia, Florian1,2 (AUTHOR) florian.pennarubia@uga.edu, Pinault, Emilie1,3 (AUTHOR) emilie.pinault@unilim.fr, Legardinier, Sébastien1 (AUTHOR) sebastien.legardinier@unilim.fr, Maftah, Abderrahman1 (AUTHOR) abderrahman.maftah@unilim.fr |
| Source: |
Cancers. Jun2020, Vol. 12 Issue 6, p1430. 1p. |
| Subject Terms: |
*CELLULAR signal transduction, *COLON tumors, *GENE expression, *MASS spectrometry, *GENETIC mutation, *TRANSFERASES, RECTUM tumors |
| Abstract: |
Background: Protein O-fucosyltransferase 1 (POFUT1) overexpression, which is observed in many cancers such as colorectal cancer (CRC), leads to a NOTCH signaling dysregulation associated with the tumoral process. In rare CRC cases, with no POFUT1 overexpression, seven missense mutations were found in human POFUT1. Methods: Recombinant secreted forms of human WT POFUT1 and its seven mutated counterparts were produced and purified. Their O-fucosyltransferase activities were assayed in vitro using a chemo-enzymatic approach with azido-labeled GDP-fucose as a donor substrate and NOTCH1 EGF-LD26, produced in E. coli periplasm, as a relevant acceptor substrate. Targeted mass spectrometry (MS) was carried out to quantify the O-fucosyltransferase ability of all POFUT1 proteins. Findings: MS analyses showed a significantly higher O-fucosyltransferase activity of six POFUT1 variants (R43H, Y73C, T115A, I343V, D348N, and R364W) compared to WT POFUT1. Interpretation: This study provides insights on the possible involvement of these seven missense mutations in colorectal tumors. The hyperactive forms could lead to an increased O-fucosylation of POFUT1 protein targets such as NOTCH receptors in CRC patients, thereby leading to a NOTCH signaling dysregulation. It is the first demonstration of gain-of-function mutations for this crucial glycosyltransferase, modulating NOTCH activity, as well as that of other potential glycoproteins. [ABSTRACT FROM AUTHOR] |
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| Database: |
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