更新于：2024-09-05

SLC39A9

更新于：2024-09-05

基本信息

别名

FLJ11274、SLC39A9、solute carrier family 39 member 9

+ [5]

简介

Transports zinc ions across cell and organelle membranes into the cytoplasm and regulates intracellular zinc homeostasis (PubMed:25014355, PubMed:19420709, PubMed:28219737). Participates in the zinc ions efflux out of the secretory compartments (PubMed:19420709). Regulates intracellular zinc level, resulting in the enhancement of AKT1 and MAPK3/MAPK1 (Erk1/2) phosphorylation in response to the BCR activation (PubMed:23505453). Also functions as membrane androgen receptor that mediates, through a G protein, the non-classical androgen signaling pathway, characterized by the activation of MAPK3/MAPK1 (Erk1/2) and transcription factors CREB1 or ATF1 (By similarity). This pathway contributes to CLDN1 and CLDN5 expression and tight junction formation between adjacent Sertoli cells (By similarity). Mediates androgen-induced vascular endothelial cell proliferation through activation of an inhibitory G protein leading to the AKT1 and MAPK3/MAPK1 (Erk1/2) activation which in turn modulate inhibition (phosphorylation) of GSK3B and CCND1 transcription (PubMed:34555425). Moreover, has dual functions as membrane-bound androgen receptor and as an androgen-dependent zinc transporter both of which are mediated through an inhibitory G protein (Gi) that mediates both MAP kinase and zinc signaling leading to the androgen-dependent apoptotic process (PubMed:25014355, PubMed:28219737).

关联

100 项与 SLC39A9 相关的临床结果

登录后查看更多信息

100 项与 SLC39A9 相关的转化医学

登录后查看更多信息

0 项与 SLC39A9 相关的专利（医药）

登录后查看更多信息

项与 SLC39A9 相关的文献（医药）

2023-12-06·Protoplasma

Elevated luteinizing hormone receptor signaling or selenium treatment leads to comparable changes in adrenal cortex histology and androgen-AR/ZIP9 signaling.

Article

作者: Jaroslaw Wieczorek ; Piotr Pawlicki ; Marta Zarzycka ; Laura Pardyak ; Piotr Niedbala ; Michal Duliban ; Begum Yurdakok-Dikmen ; Malgorzata Kotula-Balak

The importance and regulation of adrenal androgen production and signaling are not completely understood and are scarcely studied. In addition, there is still a search for appropriate animal models and experimental systems for the investigation of adrenal physiology and disease. Therefore, the main objective of the study was to evaluate the effect of luteinizing hormone (LH) signaling and selenium (Se2+) exposure on androgen adrenal signaling via canonical androgen receptor (AR), and membrane androgen receptor acting as zinc transporter (zinc- and iron-like protein 9; ZIP9). For herein evaluations, adrenals isolated from transgenic mice with elevated LH receptor signaling (KiLHRD^582G) and adrenals obtained from rabbits used for ex vivo adenal cortex culture and exposure to Se2+ were utilized. Tissues were assessed for morphological, morphometric, and Western blot analyses and testosterone and zinc level measurements.Comparison of adrenal cortex histology and morphometric analysis in KiLHRD^582G mice and Se2+-treated rabbits revealed cell hypertrophy. No changes in the expression of proliferating cell nuclear antigen (PCNA) were found. In addition, AR expression was decreased (p < 0.001) in both KiLHRD^582G mouse and Se2+-treated rabbit adrenal cortex while expression of ZIP9 showed diverse changes. Its expression was increased (P < 0.001) in KiLHRD^582G mice and decreased (P < 0.001) in Se2+-treated rabbits but only at the dose 10 ug/100 mg/ tissue. Moreover, increased testosterone levels (P < 0.05) and zinc levels were detected in the adrenal cortex of KiLHRD^582G mice whereas in rabbit adrenal cortex treated with Se2+, the effect was the opposite (P < 0.001).

2023-10-09·Biochimica et biophysica acta. Molecular cell research

METTL3 and METTL14 regulate IL-6 expression via RNA m6A modification of zinc transporter SLC39A9 and DNA methylation of IL-6 in periodontal ligament cells.

Article

作者: Jing Huang ; Yining Wang ; Yi Zhou

The inflammatory response is a key process in periodontitis. The N6-methyladenosine (m6A) modification has been proven to be involved in various physiological and pathological processes. This study aims to investigate the role and downstream mechanism of N6-adenosine-enzyme subunits methyltransferase (METTL) 3 and 14 in the inflammatory response of periodontal ligament cells (PDLCs). The total m6A content and the expression of METTL3 and METTL14 were upregulated in lipopolysaccharide (LPS)-stimulated PDLCs. Knockdown of METTL3 or METTL14 suppressed the LPS-induced interleukin (IL)-6 expression, as shown by quantitative polymerase chain reaction (qPCR) and enzyme linked immunosorbent assay (ELISA). Mechanistically, conjoint analysis of m6A sequencing of METTL3-knockdown and METTL14-knockdown PDLCs revealed that the expression of solute carrier family 39 member 9 (SLC39A9) was mediated in a m6A-dependent manner. The suppression of LPS-induced IL-6 by METTL3 or METTL14 knockdown was partially counteracted by SLC39A9 knockdown, which induced downregulation of intracellular zinc via immunofluorescence staining. Amplicon bisulfite sequencing (AmpBS) demonstrated that METTL3/14 knockdown increased the methylation at one position of the IL-6 promoter, while SLC39A9 knockdown decreased it, which was basically consistent with the intracellular zinc concentration and negatively associated with IL-6 expression. Moreover, METTL3 or METTL14 knockdown attenuated the LPS-induced phosphorylation of p38 and JNK mitogen-activated protein kinase (MAPK), which was partially counteracted by SLC39A9 knockdown. These results revealed the "LPS-METTL3/14-SLC39A9-zinc-IL-6" axis and involvement of p38 and JNK MAPK signaling pathway in the inflammatory responses of PDLCs.

2023-10-03·General and comparative endocrinology

The uterusmasculinus of the Eurasian beaver (Castor fever L.) - the appraisal of fast hormone regulation by membrane androgen and estrogen receptors involvement.

Article

作者: M Kotula-Balak ; G Lonc ; M Zarzycka ; J Tomiyasu ; K Knapczyk-Stwora ; B J Płachno ; A J Korzekwa ; J Kaczmarczyk ; I Krakowska

The phenomenon of remaining paramesonephric ducts (uterus masculinus) in males of some animal species concerning its role is still an unresolved issue. Now it is well-recognized that sex hormonal regulation of reproductive physiology involves also fast nongenomic control of cellular processes through noncanonical signaling. Herein, in the uterus masculinus of Eurasian beaver membrane androgen receptor (metal ion transporter Zrt- and Irt-like protein 9; ZIP9) and membrane estrogen receptor (G protein-coupled estrogen receptor; GPER) were studied. Scanning electron microscopy together with anatomical analysis revealed that Eurasian male beavers possess one double uterus (uterus duplex). Two odd parts open into the vagina but do not form a common lumen. The length of the horns is the most differential feature of this organ in studied animals. Uterus masculinus is not a tightly closed tubular structure. Histological analysis showed an analogy to the female uterus structure however no glands but gland-like structures were observed. The presence and abundant localization of ZIP9 and GPER proteins in cells of uterus masculinus was confirmed by immunohistochemistry while their expression was measured by western blotting. GPER expression in remnants was lower (P < 0.001) than those in the female uterus. Parallelly, the concentration of progesterone and estradiol but not testosterone was lower (P < 0.05 and P < 0.01, respectively) in comparison to the female uterus. Our study, for the first time, reports the involvement of fast hormonal regulation in the uterus masculinus of Eurasian beavers reflecting the participation of this organ in the creation local hormonal environment. Moreover, the uterus masculinus seems to be a useful research model for understanding and resolving urgent biological problems such as gender identities and having children by women with a lack of uterus or anatomical barriers on this level.

项与 SLC39A9 相关的新闻（医药）

2022-06-28

·CPhI制药在线

抗体 | 默沙东欲收购ADC重磅企业Seagen，LIV-1或成ADC突围新靶点

点击关注，星标CPhI制药在线近期，据华尔街日报报道，制药巨擘默沙东正与ADC药物上市公司Seagen讨论关于收购的交易，这一消息让Seagen的股价当天上涨了16.6%，市值一度超过310亿美元。业内人士表示交易并非迫在眉睫，并指出监管批准的挑战，可能会引发反垄断问题。如果默沙东不进行收购，两家公司可能会达成商业化合作协议。 Seagen是全球ADC（抗体偶联药物）领域的龙头公司，目前拥有3款已获批的ADC和至少5个其他在研ADC管线。此次交易并非默沙东第一次表达对Seagen的垂青。2020年9月，默沙东引进Seagen的LIV-1 ADC新药Ladiratuzumab Vedotin，同时对Seagen进行10亿美元的股权投资。 ADC赛道竞争白热化，LIV-1或成突围新靶点 ADC的基本设计思路是将抗体与细胞毒性药物通过连接子进行偶联，从而同时发挥抗体的高度特异性与细胞毒性药物对肿瘤细胞的高杀伤性。ADC被提出已有四十多年的时间，经过众多科学家不断的优化抗体、小分子毒性药物、连接子等，近两年迎来了丰收。近年来，多个ADC药物获批，对于难治性癌症取得了一系列突破，荣昌生物靶向Her2的ADC药物爱地希的成功上市，给国内ADC药物的研发注入了强心剂，将ADC药物研发再次推向高潮，潜在ADC重磅药物与靶点不断涌现。从靶点布局来看，目前ADC药物研发集中在成熟靶点，主要是已有上市ADC药物或者已在其他疗法中得到验证的靶点。其中，国内药企研发管线布局最多的靶点为Her2，其次是Trop-2靶点。与国外相比，靶点选择较为集中，后期市场竞争大。所以，差异化布局，选择其他潜力靶点已是众多ADC研发的制胜法宝。 LIV-1（也称为SLC39A6或ZIP6）属于锌转运蛋白SLC39A家族，SLC39A（ZIP）家族包含14个家族成员，分为4个亚家族：ZIP-I（ZIP9）、ZIP-II（ZIP1-3）、gufA（ZIP11）和 LIV-1（ZIP4-8，ZIP10，ZIP12-14）。所有的SLC39A转运蛋白都有5到8个跨膜结构域，具有转运锌（Zn）离子的功能。锌离子涉及到生命的许多方面，包括DNA复制、转录、蛋白质合成、细胞增殖、细胞凋亡和信号传导等重要方面。细胞内的锌水平受到特定的锌转运蛋白的严格调控。目前已知哺乳动物有两个互补的锌转运蛋白家族（SLC39A和SLC30A）直接参与细胞内锌离子的稳态代谢。SLC39A家族已被证明可促进细胞外或细胞器内的锌离子转运到细胞质，SLC30A家族（ZnT家族）与SLC39A家族功能相反，多个家族成员可协助锌离子从细胞质内流出到细胞外或流进到细胞器内。目前已经发现，LIV-1在乳腺癌、前列腺癌、胰腺癌、宫颈癌和肝癌等多种肿瘤细胞中高表达而在正常组织有限表达，从而成为ADC治疗的有希望的候选者并且很有可能成为某些癌症的预后及检测指标。乳腺癌是女性最常见的恶性肿瘤，与正常的乳腺组织相比，锌离子在乳腺肿瘤细胞中有较高富集，LIV-1是乳腺癌细胞中发现的第一个可受雌激素诱导表达的锌离子转运蛋白，所以它被认为与乳腺癌的发生和发展密切相关。而且LIV-1既可以通过其作为锌转运蛋白的功能在细胞生长中发挥作用，又通过与基质金属蛋白酶的结合而在乳腺癌的转移中发挥作用。 Ladiratuzumab vedotin临床试验数据 Ladiratuzumab vedotin由一种LIV-1靶向单克隆抗体与一种有效的微管破坏剂-单甲基auristatin E（MMAE），通过蛋白酶可裂解的连接器连接。这种新型ADC被设计成与癌细胞上的LIV-1结合，一旦内化，将释放杀细胞剂到靶细胞中。在2021年的ESMO年会上，公布了Ladiratuzumab vedotin的临床数据。在接受Ladiratuzumab vedotin 1.25 mg/kg 的29例转移性三阴性（mTNBC）患者中，客观缓解率为28%。药代动力学分析表明，与q3w给药相比，q1w给药降低了峰谷波动，降低了Cmax，同时保持较高的Ctrough。目前，Ladiratuzumab vedotin正在进行II期临床试验，用于联合派姆单抗（pembrolizumab）治疗三阴性和HER-2阴性乳腺癌，以及作为单药疗法治疗不能切除的局部晚期或转移性实体肿瘤。 ADC药物这两年获得飞速发展，国内也有众多企业加入研发行列。截至2021年8月，全球处于活跃状态的ADC药物共288个，其中已上市13个，处于早期临床阶段的高达186个。目前ADC药物研发存在靶点拥挤的现象，因此如何布局、如何差异化竞争考验着每一家创新型药企。寻找新靶点成为差异化布局的关键，LIV-1就是一个新希望。参考来源： 1. Sussman D, et al. (2014). SGN-LIV1A: a development stage antibody drug-conjugate targeting LIV-1 for the treatment of metastatic breast cancer. 2. Kuan-Lin Wu, Chenfei Yu, Catherine Lee et al.Precision Modification of Native Antibodies.Bioconjugate Chem 2022. 3. Stephen J. Walsh, Soleilmane Omarjee, Warren R. J. D. Galloway et al.A general approach for the site-selective modification of native proteins, enabling the generation of stable and functional antibody-drug conjugates.Chem.Sci.2019. 智药研习社小程序上线，三重福利扫码领取！来源：CPhI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多精彩制药资讯，请关注CPhI制药在线▼点击阅读原文，进入智药研习社~

抗体药物偶联物抗体并购合作小分子药物