Role of the kringle-like domain in glycoprotein NMB for its tumorigenic potential.

Autor: Xie R; Department of Experimental Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.; Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan., Okita Y; Department of Experimental Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.; Division of Cell Dynamics, Transborder Medical Research Center, University of Tsukuba, Tsukuba, Japan., Ichikawa Y; Department of Experimental Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.; Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan., Fikry MA; Department of Experimental Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.; Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan., Huynh Dam KT; Department of Experimental Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.; Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan., Tran STP; Department of Experimental Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.; Human Biology, School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Japan., Kato M; Department of Experimental Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.; Division of Cell Dynamics, Transborder Medical Research Center, University of Tsukuba, Tsukuba, Japan.
Jazyk: angličtina
Zdroj: Cancer science [Cancer Sci] 2019 Jul; Vol. 110 (7), pp. 2237-2246. Date of Electronic Publication: 2019 Jun 26.
DOI: 10.1111/cas.14076
Abstrakt: Glycoprotein NMB (GPNMB) is highly expressed in many types of malignant tumors and thought to be a poor prognostic factor in those cancers, including breast cancer. Glycoprotein NMB is a type IA transmembrane protein that has a long extracellular domain (ECD) and a short intracellular domain (ICD). In general, the ECD of a protein is involved in protein-protein or protein-carbohydrate interactions, whereas the ICD is important for intracellular signaling. We previously reported that GPNMB contributes to the initiation and malignant progression of breast cancer through the hemi-immunoreceptor tyrosine-based activation motif (hemITAM) in its ICD. Furthermore, we showed that the tyrosine residue in hemITAM is involved in induction of the stem-like properties of breast cancer cells. However, the contribution of the ECD to its tumorigenic function has yet to be fully elucidated. In this study, we focused on the region, the so-called kringle-like domain (KLD), that is conserved among species, and made a deletion mutant, GPNMB(ΔKLD). Enhanced expression of WT GPNMB induced sphere and tumor formation in breast epithelial cells; in contrast, GPNMB(ΔKLD) lacked these activities without affecting its molecular properties, such as subcellular localization, Src-induced tyrosine phosphorylation at least in overexpression experiments, and homo-oligomerization. Additionally, GPNMB(ΔKLD) lost its cell migration promoting activity, even though it reduced E-cadherin expression. Although the interaction partner binding to KLD has not yet been identified, we found that the KLD of GPNMB plays an important role in its tumorigenic potential.
(© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
Databáze: MEDLINE