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更新于：2025-05-07

NLK

更新于：2025-05-07

基本信息

别名

LAK1、nemo like kinase、nemo-like kinase

+ [3]

简介

Serine/threonine-protein kinase that regulates a number of transcription factors with key roles in cell fate determination (PubMed:12482967, PubMed:14960582, PubMed:15004007, PubMed:15764709, PubMed:20061393, PubMed:20874444, PubMed:21454679). Positive effector of the non-canonical Wnt signaling pathway, acting downstream of WNT5A, MAP3K7/TAK1 and HIPK2 (PubMed:15004007, PubMed:15764709). Negative regulator of the canonical Wnt/beta-catenin signaling pathway (PubMed:12482967). Binds to and phosphorylates TCF7L2/TCF4 and LEF1, promoting the dissociation of the TCF7L2/LEF1/beta-catenin complex from DNA, as well as the ubiquitination and subsequent proteolysis of LEF1 (PubMed:21454679). Together these effects inhibit the transcriptional activation of canonical Wnt/beta-catenin target genes (PubMed:12482967, PubMed:21454679). Negative regulator of the Notch signaling pathway (PubMed:20118921). Binds to and phosphorylates NOTCH1, thereby preventing the formation of a transcriptionally active ternary complex of NOTCH1, RBPJ/RBPSUH and MAML1 (PubMed:20118921). Negative regulator of the MYB family of transcription factors (PubMed:15082531). Phosphorylation of MYB leads to its subsequent proteolysis while phosphorylation of MYBL1 and MYBL2 inhibits their interaction with the coactivator CREBBP (PubMed:15082531). Other transcription factors may also be inhibited by direct phosphorylation of CREBBP itself (PubMed:15082531). Acts downstream of IL6 and MAP3K7/TAK1 to phosphorylate STAT3, which is in turn required for activation of NLK by MAP3K7/TAK1 (PubMed:15004007, PubMed:15764709). Upon IL1B stimulus, cooperates with ATF5 to activate the transactivation activity of C/EBP subfamily members (PubMed:25512613). Phosphorylates ATF5 but also stabilizes ATF5 protein levels in a kinase-independent manner (PubMed:25512613). Acts as an inhibitor of the mTORC1 complex in response to osmotic stress by mediating phosphorylation of RPTOR, thereby preventing recruitment of the mTORC1 complex to lysosomes (PubMed:26588989).

关联

项与 NLK 相关的药物

OTS-167

靶点

NLK x hMELK

作用机制

MELK抑制剂 [+1]

在研机构

OncoTherapy Science, Inc. [+1]

原研机构

OncoTherapy Science, Inc.

在研适应症

晚期乳腺癌 [+3]

非在研适应症

急性淋巴细胞白血病 [+7]

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

CC-91516

靶点

ERK1 x ERK2 x NLK

作用机制

ERK1抑制剂 [+2]

在研机构

Bristol Myers Squibb Co.

原研机构

Bristol Myers Squibb Co.

在研适应症

肿瘤

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 NLK 相关的临床试验

JPRN-jRCT2031230090

/ Recruiting临床1期IIT

A Phase I Study of OTS167PO, a MELK inhibitor, to Evaluate Safety, Tolerability and Pharmacokinetics in Patients with Advanced Breast Cancer and Dose-Expansion Study in Patients with Triple Negative Breast Cancer. - OTS1070103

开始日期2021-03-02

申办/合作机构-

NCT02926690

/ Active, not recruiting临床1期

A Phase I Study of OTS167PO, a MELK Inhibitor, to Evaluate Safety, Tolerability and Pharmacokinetics in Patients with Advanced Breast Cancer and Dose-Expansion Study in Patients with Triple Negative Breast Cancer

The purpose of this study is to determine the maximum tolerated dose (MTD) of OTS167 administered via oral capsule (PO) to patients with relapsed/refractory locally advanced or metastatic breast cancer.

开始日期2017-05-29

申办/合作机构

OncoTherapy Science, Inc.

ACTRN12616000043437

/ Completed临床1期IIT

A phase 1, randomised, placebo-controlled, double-blind, cross-over study to evaluate systemic bioavailability of oral OTS167 under fed and fasting conditions in healthy adult subjects.

开始日期2016-01-11

申办/合作机构-

100 项与 NLK 相关的临床结果

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100 项与 NLK 相关的转化医学

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0 项与 NLK 相关的专利（医药）

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285

项与 NLK 相关的文献（医药）

2025-06-01·SLAS Technology

Identifcation of the FGF family as therapeutic targets and prognostic biomarkers in the microenvironment of head and neck squamous cell carcinoma

Article

作者: Wei, Jian ; Xu, Yingjiao ; Gao, Yingchun ; Zhang, Xuan ; Tian, Yumei ; Liu, Xuqian ; Nie, Minhai ; Zhang, Li

BACKGROUNDAlmost 90 % of head and neck malignancies are malignant squamous cell cancers, making it the sixth most common malignancy in the developing countries, with an overall five-year overall survival rate about 40 %-50 %. Early diagnosis and treatment can bring a better prognosis. Fibroblast growth factor (FGF) is an important polypeptide in vivo. Studies have found that FGF signal has carcinogenic potential and participates in a variety of carcinogenic behaviors. Some experiments have proved that FGF signal has the function of tumor inhibition in some cases, and the role of FGF signalling in tissue repair and homeostasis suggest a role for FGF in targeted therapy and prognosis. However, its manifestation and predictive role in HNSC have not been clearly defined.METHODSGenome-wide expression analysis of Oncomine evaluated the evaluation of FGF family expression in HNSC. Expression analysis and HNSC data set were used to obtain FGF family expression data and T statistic was applied for analysis. The differential mRNA expression levels in tumor versus normal tissues, as well as the correlation with pathological staging and prognosis, were examined using the GEPIA single-gene analysis tool for the FGF family.FGF family altered CO expression and network modules were obtained from cBioportal and analyzed in 520 HNSC samples.Pro-protein interaction (PPI) flow network is performed on the differentially ordered FGF clusters using STRING, Gene Operating System (GO) domain domain enrichment as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis are performed on the FGF cluster and its neighbouring genes using DAVID6.8, key transcriptional factors (TF) of FGF family was analyzed by TRRUST, correlation between FGF family level and autoimmune cell migration was evaluated by TIMER, and biological analysis of FGF family kinase target enrichment was performed using LinkInterpreter.RESULTSOnly the expression of FGF6 in HNSC was down-regulated in all FGF family(FC=2),Transcriptional level of FGF1, FGF2, FGF5, FGF7-14, FGF17-19, FGF21 and FGF22 was upregulated in HNSC .In terms of the relative level of FGF family in HNSC, the greatest amount of FGF11. In different pathological stages of HNSC, the expression of FGF was meaningless (P>0.05), and FGF3-6, FGF8-10, FGF14, FGF16, FGF17, FGF1921, FGF23 showed no significant difference in different HNSC stages. Low expression of FGF5 and high expression of FGF22 had low overall survival(OS) rate of HNSC(P =0.012, P =0.0015). In addition, enrichment analysis of FGF family in HNSC showed that it was highly abundant in PI3K-Akt signaling pathway, MAPK and rasper pathway. Our data showed that ATF4, STAT, RELA, NFKB1 are key transcription target of the FGF family, NLK, LOCK1, LYN, ZAP70, MAP2K3, RPS6KA4, AURKB, ATR, ROCK1, MYLK2, CAMK2A, EGFR, MAPK3, MAP3K8, SYK, LCK, HCK, PKN2, RPS6KA1, BUB1, CDK5, ITK, FYN, TBK1, ATM, CDK2, PTK2 are kinase targets of the FGF family. We identified a relationship between the modulation of FGF expression and cellular infiltration, such as B lymphocytes, CD4+ T cells and macrophages dendritic cells.CONCLUSIONSOur data may shed new light on the choice of immunotherapeutic targets and predictive biomarkers in HNSC.

2025-04-18·Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences

[Gene silencing of Nemo-like kinase promotes neuralized tissue engineered bone regeneration].

Article

作者: Lei, Lei ; Li, Mengdi ; Jiang, Ting ; Liu, Zhongning ; Li, Jian

OBJECTIVETo identify the role of gene silencing or overexpression of Nemo-like kinase (NLK) during the process of neural differentiation of human mesenchymal stem cells (hBMSCs), and to explore the effect of NLK downregulation by transfection of small interfering RNA (siRNA) on promoting neuralized tissue engineered bone regeneration.METHODSNLK-knockdown hBMSCs were established by transfection of siRNA (the experimental group was transfected with siRNA silencing the NLK gene, the control group was transfected with control siRNA and labeled as negative control group), and NLK-overexpression hBMSCs were established using lentivirus vector transfection technique (the experimental group was infected with lentivirus overexpressing the NLK gene, the control group was infected with an empty vector lentivirus and labeled as the empty vector group). After neurogenic induction, quantitative real-time polymerase chain reaction (qPCR) was used to detect the expression of neural-related gene, and Western blot as well as immunofluorescence staining about several specific neural markers were used to evaluate the neural differentiation ability of hBMSCs.6-week-old male nude mice were divided into 4 groups: ① β-tricalcium phosphate (β-TCP) group, ② β-TCP+ osteogenic induced hBMSCs group, ③ β-TCP+ siRNA-negative control (siRNA-NC) transfection hBMSCs group, ④ β-TCP+ siRNA-NLK transfection hBMSCs group. Four weeks after the subcutaneous ectopic osteogenesis models were established, the osteogenesis and neurogenesis were detected by hematoxylin-eosin (HE) staining, Masson staining and tissue immunofluorescence assay. Statistical analysis was conducted by independent sample t test.RESULTSAfter gene silencing of NLK by siRNA in hBMSCs, neural-related genes, including the class Ⅲ β-tubulin (TUBB3), microtubule association protein-2 (MAP2), soluble protein-100 (S100), nestin (NES), NG2 proteoglycan (NG2) and calcitonin gene-related peptide (CGRP), were increased significantly in NLK-knockdown hBMSCs compared with the negative control group(P < 0.05), and the expression levels of TUBB3 and MAP2 of the NLK silencing group were also increased. Oppositely, after NLK was overexpressed using lentivirus vector transfection technique, TUBB3, MAP2, S100 and NG2 were significantly decreased in NLK-overexpression hBMSCs compared with the empty vector group (P < 0.05), and the expression level of TUBB3 was also decreased. 4 weeks after the subcutaneous ectopic osteogenesis model was established, more mineralized tissues were formed in the β-TCP+ siRNA-NLK transfection hBMSCs group compared with the other three groups, and the expression of BMP2 and S100 was higher in the β-TCP+ siRNA-NLK transfection hBMSCs group than in the other groups.CONCLUSIONGene silencing of NLK by siRNA promoted the ability of neural differentiation of hBMSCs in vitro and promoted neuralized tissue engineered bone formation in subcutaneous ectopic osteogenic models in vivo in nude mice.

2025-03-01·Development

EFL-3/E2F7 modulates Wnt signalling by repressing the Nemo-like kinase LIT-1 during asymmetric epidermal cell division in Caenorhabditis elegans

Article

作者: Barkoulas, Michalis ; Ferrando-Marco, Mar

ABSTRACTThe E2F family of transcription factors is conserved in higher eukaryotes and plays pivotal roles in controlling gene expression during the cell cycle. Most canonical E2Fs associate with members of the Dimerisation Partner (DP) family to activate or repress target genes. However, atypical repressors, such as E2F7 and E2F8, lack DP interaction domains and their functions are less understood. We report here that EFL-3, the E2F7 homologue of Caenorhabditis elegans, regulates epidermal stem cell differentiation. We show that phenotypic defects in efl-3 mutants depend on the Nemo-like kinase LIT-1. EFL-3 represses lit-1 expression through direct binding to a lit-1 intronic element. Increased LIT-1 expression in efl-3 mutants reduces POP-1/TCF nuclear distribution, and consequently alters Wnt pathway activation. Our findings provide a mechanistic link between an atypical E2F family member and NLK during C. elegans asymmetric cell division, which may be conserved in other animals.