Role of the kringle‐like domain in glycoprotein NMB for its tumorigenic potential
Role of the kringle‐like domain in glycoprotein NMB for its tumorigenic potential
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DOI：
10.1111/cas.14076
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发表时间：
2019-06
期刊：
影响因子：
5.7
通讯作者：
Rudy Xie;Yukari Okita;Y. Ichikawa;Muhammad Ali Fikry;Kim Tuyen Huynh Dam;S. T. P. Tran;Mitsuyasu Kato
中科院分区：
文献类型：
--
作者：
Rudy Xie;Yukari Okita;Y. Ichikawa;Muhammad Ali Fikry;Kim Tuyen Huynh Dam;S. T. P. Tran;Mitsuyasu Kato
糖蛋白NMB （GPNMB）在许多类型的恶性肿瘤中高度表达，并被认为是包括乳腺癌在内的这些癌症的预后不良因素。糖蛋白NMB是一种具有长胞外结构域（ECD）和短胞内结构域（ICD）的IA型跨膜蛋白。一般来说，蛋白质的ECD参与蛋白质-蛋白质或蛋白质-碳水化合物的相互作用，而ICD对细胞内信号传导很重要。我们之前报道过GPNMB通过其ICD中基于半免疫受体酪氨酸的激活基序（hemITAM）参与乳腺癌的发生和恶性进展。此外，我们发现hemITAM中的酪氨酸残基参与了乳腺癌细胞干细胞样特性的诱导。然而，ECD对其致瘤功能的贡献尚未完全阐明。在这项研究中，我们专注于该区域，即所谓的kringle - like domain (KLD)，该区域在物种之间是保守的，并制作了一个缺失突变体GPNMB（ΔKLD）。WT - GPNMB诱导乳腺上皮细胞球形及肿瘤形成的增强表达相比之下，GPNMB（ΔKLD）缺乏这些活性，但不影响其分子特性，如亚细胞定位、Src诱导的酪氨酸磷酸化（至少在过表达实验中）和同源寡聚化。此外，GPNMB（ΔKLD）失去了促进细胞迁移的活性，尽管它降低了E‐cadherin的表达。虽然与KLD结合的相互作用伙伴尚未确定，但我们发现GPNMB的KLD在其致瘤潜能中起重要作用。
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.