RRC ID 57734
Author Mizuta H, Kuga K, Suzuki T, Niwa Y, Dohmae N, Simizu S.
Title C‑mannosylation of R‑spondin2 activates Wnt/β‑catenin signaling and migration activity in human tumor cells.
Journal Int J Oncol
Abstract R‑spondin2 (Rspo2), one of the four members of the R‑spondin family of proteins, has agonistic activity in the Wnt/β‑catenin signaling pathway, and it is associated with normal development, as well as disease, such as cancer. The present study focused on the C‑mannosylation of Rspo2, which is a novel and unique type of glycosylation that occurs via a C‑C linkage between the tryptophan residue and an α‑mannose. Although Rspo2 has two putative C‑mannosylation sites at residues Trp150 and Trp153, it had not been reported to date whether these sites are C‑mannosylated. Firstly, results from mass spectrometry demonstrated that Rspo2 was C‑mannosylated at the Trp150 and Trp153 residues. Notably, while this C‑mannosylation of Rspo2 resulted in increased extracellular secretion in human fibrosarcoma HT1080 cells, in other human tumor cell lines it inhibited secretion. However, C‑mannosylation had consistent effects on the activation of Wnt/β‑catenin signaling in PANC1 and MDA‑MB‑231 cells, as well as HT1080 cells. Furthermore, overexpression of wild‑type Rspo2 significantly increased the migratory ability of A549 and HT1080 cells, whereas overexpression of a C‑mannosylation‑defective mutant enhanced migration to a lesser degree. These results suggested that C‑mannosylation of Rspo2 may promote cancer progression and that the inhibition of C‑mannosylation may serve as a potential novel therapeutic approach for cancer therapy.
Volume 54(6)
Pages 2127-2138
Published 2019-6-1
DOI 10.3892/ijo.2019.4767
PMID 30942431
MeSH Cell Line, Tumor Cell Movement* Humans Intercellular Signaling Peptides and Proteins / metabolism* Mannose / metabolism Mannosyltransferases / metabolism Neoplasms / pathology* Tryptophan / metabolism Wnt Signaling Pathway* beta Catenin / metabolism
IF 3.899
Times Cited 5
Human and Animal Cells 293T(RCB2202) A549