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更新于：2025-05-07

NEDD9

更新于：2025-05-07

基本信息

别名

Cas scaffolding protein family member 2、CAS-L、CasL

+ [11]

简介

Scaffolding protein which plays a central coordinating role for tyrosine-kinase-based signaling related to cell adhesion (PubMed:24574519). As a focal adhesion protein, plays a role in embryonic fibroblast migration (By similarity). May play an important role in integrin beta-1 or B cell antigen receptor (BCR) mediated signaling in B- and T-cells. Integrin beta-1 stimulation leads to recruitment of various proteins including CRKL and SHPTP2 to the tyrosine phosphorylated form (PubMed:9020138). Promotes adhesion and migration of lymphocytes; as a result required for the correct migration of lymphocytes to the spleen and other secondary lymphoid organs (PubMed:17174122). Plays a role in the organization of T-cell F-actin cortical cytoskeleton and the centralization of T-cell receptor microclusters at the immunological synapse (By similarity). Negatively regulates cilia outgrowth in polarized cysts (By similarity). Modulates cilia disassembly via activation of AURKA-mediated phosphorylation of HDAC6 and subsequent deacetylation of alpha-tubulin (PubMed:17604723). Positively regulates RANKL-induced osteoclastogenesis (By similarity). Required for the maintenance of hippocampal dendritic spines in the dentate gyrus and CA1 regions, thereby involved in spatial learning and memory (By similarity).

关联

项与 NEDD9 相关的药物

Fisetin

漆黄素

靶点

NEDD9 x mTOR

作用机制

NEDD9 inhibitors [+1]

在研机构

University of Wisconsin Madison [+2]

原研机构

Mayo Clinic

在研适应症

系统性硬化相关的间质性肺病 [+8]

非在研适应症-

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

Isorhapontigenin

靶点

MEG3 x NEDD9

作用机制

MEG3 激动剂 [+1]

在研机构

New York University School of Medicine

原研机构

New York University School of Medicine

在研适应症

肺癌

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 NEDD9 相关的临床试验

NCT05505747

/ Not yet recruiting临床2/3期IIT

Enhancing Recovery Through a Combined Mechanobiologic Intervention Following Meniscus Repair

Arthroscopic meniscal procedures are the most commonly performed orthopaedic procedure in the U.S. affecting 15% of Americans ages 10-65 years. Meniscus injury is also known to increase the risk of posttraumatic osteoarthritis (PTOA). The current randomized clinical trial will test a novel intervention after meniscal repair that combines an oral senolytic fisetin and real-time biofeedback program to restore joint loading and subsequent return to activity.

开始日期2025-07-01

申办/合作机构

University of Kentucky

NCT06796374

/ Not yet recruitingN/AIIT

A Comparison of Fisetin Kinetics in Young and Old Adults - FISEKIN-1

This study investigates the differences in the kinetic parameters of fisetin in two cohorts of healthy volunteers:
Cohort 1) volunteers aged 18-30 years (n = 40) Cohort 2) volunteers aged 65 years or older (n = 40)
The purpose of this study is:
1. To describe the fisetin kinetics after a single dose oral administration in older age.
2. To compare the fisetin kinetics after a single dose oral administration in old and young age.
FISEKIN-1 is designed as a four-arm study protocol. As well as two different age groups (18-30 years vs. 65 years and older), we want to compare fisetin kinetic parameters in two different fisetin formulations and dosages :
Arm 1) 100 mg fisetin (1x 1 capsule), cohort 1: young age Arm 2) 100 mg fisetin (1x 1 capsule), cohort 2: old age Arm 3) 1000 mg fisetin + 200 mg quercetin (2x 1 softgel capsule), cohort 1: young age Arm 4) 1000 mg fisetin + 200 mg quercetin (2x 1 softgel capsule), cohort 2: old age

开始日期2025-02-01

申办/合作机构

University of Greifswald

NCT06431932

/ Not yet recruiting临床1/2期IIT

Pharmacokinetics, Safety, and Efficacy of Fisetin - A Phase I and Pilot Phase IIa Study

The accumulation of senescent cells with age is a central mechanism that contributes to the development of chronic diseases, primarily by driving systemic chronic inflammation. Senolytic compounds such as fisetin can selectively target senescent cells for elimination and reduce multiple age-related pathologies in animal models.
We will conduct a clinical trial in healthy volunteers and older patients with multiple chronic diseases. The participants will receive fisetin or placebo for two days, after which they will be examined at regular intervals for up to three months. We will investigate how fisetin is absorbed and metabolized by the body, and whether fisetin is safe. We will also identify methods to best measure the effect of fisetin on chronic inflammation, senescent cells, and general health.

开始日期2025-01-01

申办/合作机构

Hvidovre University Hospital

[+2]

100 项与 NEDD9 相关的临床结果

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100 项与 NEDD9 相关的转化医学

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0 项与 NEDD9 相关的专利（医药）

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432

项与 NEDD9 相关的文献（医药）

2025-01-01·Chemico-Biological Interactions

Withaferin-A induced vimentin S56 phosphorylation dissociates NEDD9 signaling loop to regress progressive metastatic melanoma into lung adenocarcinoma

Article

作者: Prabhakar, B T ; Thirusangu, Prabhu ; Pavan Kumar, G S ; Siddesh, B M ; Kiran, B K ; Suchetha Kumari, N ; Sherapura, Ankith

Metastasis is complex and insidious type of disease involves multiple signaling nexus, which have implications in understanding disease pathogenesis. Treatment failure for metastatic cancer is frequently high due to aggressive adaptation of cancerous cells to invade to neighboring organs. Cytoskeleton intermediate filamentous protein Vimentin and scaffolding protein Neural precursor cell expressed Developmentally Down-regulated protein 9 (NEDD9) play a key role in metastatic events by regulating multiple metastatic events. Interaction between these proteins is necessary to promote metastatic progression. Withaferin A (WFA), a natural pharamacophore, known to target Vimentin to induce antitumor potential. However exact molecular mechanism still yet to be elucidated. We hypothesize, Vimentin-NEDD9 signaling nexus is necessary for metastatic progression and targeting this interwoven signaling loop with effective pharamacophore WFA halts metastatic progression of melanoma into lung. To elucidate the same, we carried out gene expression measurement through quantitative Reverses Transcription Polymerase Chain Reaction (qRT-PCR), Immunoblot and Immunohistochemistry. Assessment of interactive signaling by Co-immunoprecipitation, Immunofluorescence, Co-localization and Proximity ligation assay. Phosphorylation studies through transfection of phospho specific mutant constructs generated through site directed mutagenesis. WFA induced cellular behavioral changes by migration, invasion assays and Immunoblot analysis. The B16F10 induced mouse metastatic melanoma model to asses NEDD9-Vimentin expression and anti-metastasis induced by WFA. The results postulates, elevated levels and interaction between NEDD9-Vimentin proteins, have positive correlation in metastatic progression of melanoma into lung in both in-vitro and in-vivo condition, establishing it as therapeutic target. Pharmacologically, WFA targets this complex by extending its activity by not only inducing specific Serine 56 phosphorylation of Vimentin, also dissociates NEDD9 signaling loop to halt Epithelial-mesenchymal transition (EMT) and subsequent metastatic events. Eventually, modulation of the relevant metastatic genes E-Cadherin, N-Cadherin, SNAIL, MMP-2 & MMP-9 resulted in regression of metastatic melanoma progression to lung. The study validates WFA induced S56 phosphorylation is necessary to abrupt the NEDD9-Vimentin metastatic signaling complex to regress aggressive metastatic melanoma. The investigation emphasized more mechanistic approach of WFA. Understanding and targeting such integrative mechanical input in the tumor microenvironment will be a better therapeutic strategy to combat metastasis.

2024-11-05·Stem Cells

Hepatocyte growth factor facilitates the repair of spinal cord injuries by driving the chemotactic migration of mesenchymal stem cells through the β-catenin/TCF4/Nedd9 signaling pathway

Article

作者: Yan, Mengwen ; Chen, Huanhuan ; Yang, Ying ; Zhang, Huanxiang ; Ji, Zhongqing ; He, Qisheng ; Xu, Jianwei ; Yang, Min ; Hu, Ya’nan ; Xu, Xiaojing ; Liu, Jinming

AbstractTransplanted mesenchymal stem cells (MSCs) can significantly aid in repairing spinal cord injuries (SCIs) by migrating to and settling at the injury site. However, this process is typically inefficient, as only a small fraction of MSCs successfully reach the target lesion area. During SCI, the increased expression and secretion of hepatocyte growth factor (HGF) act as a chemoattractant that guides MSC migration. Nonetheless, the precise mechanisms by which HGF influences MSC migration are not fully understood. This study focused on unraveling the molecular pathways that drive MSC migration toward the SCI site in response to HGF. It was found that HGF can activate β-catenin signaling in MSCs by either phosphorylating LRP6, suppressing GSK3β phosphorylation through the AKT and ERK1/2 pathways, or enhancing the expression and nuclear translocation of TCF4. This activation leads to elevated Nedd9 expression, which promotes focal adhesion formation and F-actin polymerization, facilitating chemotactic migration. Transplanting MSCs during peak HGF expression in injured tissues substantially improves nerve regeneration, reduces scarring, and enhances hind limb mobility. Additionally, prolonging HGF release can further boost MSC migration and engraftment, thereby amplifying regenerative outcomes. However, inhibiting HGF/Met or interfering with β-catenin or Nedd9 signaling significantly impairs MSC engraftment, obstructing tissue repair and functional recovery. Together, these findings provide a theoretical basis and practical strategy for MSC transplantation therapy in SCI, highlighting the specific molecular mechanisms by which HGF regulates β-catenin signaling in MSCs, ultimately triggering their chemotactic migration.

2024-11-01·Neoplasia

NEDD9 is transcriptionally regulated by HDAC4 and promotes breast cancer metastasis and macrophage M2 polarization via the FAK/NF-κB signaling pathway

Article

作者: Liu, Wenhong ; Luo, Guanghua

BACKGROUNDBreast cancer is a malignancy with a generally poor prognosis. With the advancement of molecular research, we have gained deeper insights into the cellular processes that drive breast cancer development. However, the precise mechanisms remain elusive.RESULTSBased on the CPTAC database, we found that NEDD9 expression is up-regulated in breast cancer tissues and is associated with poor prognosis in breast cancer patients. Functional experiments showed that NEDD9 promotes tumor growth and metastasis both in vitro and in vivo. Overexpression of NEDD9 disrupts mammary epithelial acinus formation and triggers epithelial-mesenchymal transition in breast cancer cells, effects that are reversed upon NEDD9 gene silencing. Mechanistically, NEDD9 upregulates its expression by inhibiting HDAC4 activity, leading to enhanced H3K9 acetylation of the NEDD9 gene promoter and activation of the FAK/NF-κB signaling pathway. Furthermore, NEDD9 overexpression promotes IL-6 secretion, which further drives breast cancer progression. Notably, NEDD9 activation fosters the pro-tumoral M2 macrophage polarization in the tumor microenvironment. NEDD9 stimulates IL-6 secretion, polarizes monocytes towards an M2-like phenotype, and enhances BC cell invasiveness.CONCLUSIONSThese findings suggest that NEDD9 upregulation plays a pivotal role in breast cancer metastasis and macrophage M2 polarization via the FAK/NF-κB signaling axis. Targeting NEDD9 may offer a promising therapeutic approach for breast cancer treatment.

项与 NEDD9 相关的新闻（医药）

2023-01-30

·生物谷

STTT：组蛋白去乙酰酶抑制剂通过上调NEDD9的表达促进乳腺癌转移

组蛋白脱乙酰酶(HDACs)对组蛋白赖氨酸残基进行脱乙酰化，重塑染色质，在基因转录中发挥重要作用。组蛋白脱乙酰酶(HDACs)对组蛋白赖氨酸残基进行脱乙酰化，重塑染色质，在基因转录中发挥重要作用。由于在多种癌症亚型中的过度表达和异常活性，HDAC被认为是一个有前景的成功的抗癌药物靶点，并且已经被证明是一个成功的靶点。目前，几种HDAC抑制剂已被FDA批准用于治疗血液系统恶性肿瘤，包括伏立诺(SAHA)、贝力诺(PXD-101)、罗米迪辛(FK-228)和潘诺比坦(LBH589)。然而，HDAC抑制剂在治疗实体瘤方面的成功有限。图片来源：https://doi.org/10.1038/s41392-022-01221-6 近日，来自中国科学院的研究者们在Signal Transduction and Targeted Therapy杂志上发表了题为“Histone deacetylase inhibitors promote breast cancer metastasis by elevating NEDD9 expression”的文章，该研究证明了FAK抑制剂可以逆转通过PAN-HDAC抑制剂上调NEDD9诱导的乳腺癌转移，这可能为乳腺癌提供一种潜在的联合治疗方法。组蛋白脱乙酰酶(HDAC)是一种通过修饰组蛋白来调节基因表达的蛋白水解酶，在肿瘤中常被异常激活。已批准的PAN-HDAC抑制剂已显示出对某些血液系统恶性肿瘤患者的临床益处。在临床试验中，只观察到乳腺癌的治疗成功有限。在这项研究中，研究者宣布针对NEDD9-FAK通路的PAN-HDAC抑制剂在临床前模型中加剧了乳腺癌的转移，这可能严重阻碍其临床成功。NEDD9不是一个癌基因，但最近研究表明，NEDD9在白血病、结肠癌、乳腺癌等多种癌症中都存在高水平或高活性的变化。机制上，PAN-HDAC抑制剂通过抑制HDAC4活性，促进NEDD9基因启动子上的H3K9乙酰化，从而增加NEDD9的表达，进而激活FAK磷酸化。PAN-HDAC抑制剂可以通过增加侵袭性来改变乳腺癌的自然病程，这一认识值得临床关注。此外，尽管NEDD9被报道与乳腺癌的转移有关，但它并没有受到太多的关注，也没有开发出治疗策略。 HDAC4抑制对乳腺肿瘤细胞中NEDD9调控的示意图有助于乳腺转移图片来源：https://doi.org/10.1038/s41392-022-01221-6 综上所述，研究者发现抑制HDAC4激活了NEDD9-FAK信号通路，导致乳腺癌细胞的转移，从而限制了PAN-HDAC抑制剂对乳腺癌的临床疗效。本研究的结果强调了选择性HDAC抑制剂研究和开发的重要性。值得注意的是，FAK抑制剂被发现可以逆转由非特异性HDAC抑制剂诱导的乳腺转移，尽管还需要进一步的证据。（生物谷 Bioon.com）参考文献 Zonglong Hu et al. Histone deacetylase inhibitors promote breast cancer metastasis by elevating NEDD9 expression. Signal Transduct Target Ther. 2023 Jan 6;8(1):11. doi: 10.1038/s41392-022-01221-6.