NLK

Official Full Name

nemo like kinase

Organism

Homo sapiens

GeneID

51701

Background

Enables DNA-binding transcription factor binding activity; protein serine/threonine kinase activity; and ubiquitin protein ligase binding activity. Involved in several processes, including negative regulation of TORC1 signaling; protein stabilization; and transforming growth factor beta receptor signaling pathway. Predicted to be located in cytosol and nucleoplasm. Predicted to be active in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Feb 2025]

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Detailed Information

Nemo-like kinase (NLK) is an evolutionarily highly conserved MAPK-like kinase that is widely distributed in various tissues and organs of the body. Many studies have found that NLK can participate in the growth, differentiation, proliferation and apoptosis of tumor cells by regulating a variety of signaling pathway molecules such as Wnt/β-catenin, c-Myb, and caspase-3. Abnormally expressed NLK plays an important role in the development of neoplastic diseases and in judging the prognosis of the disease.

NLK Related Signaling Pathway

NLK exists in many signal paths, the most important of which is the Wnt/Wg signal path. Studies have shown that NLK plays an important role in the regulation of cell growth, differentiation, embryo development and tumorigenesis and development by negatively regulating the classical Wnt/β-catenin pathway by phosphorylated T-cell factor/lymphocyte enhancer family members. NLK affects the phosphorylation signal transduction and activator of transcription 3 (STAT3), and is involved in transforming growth factor beta (TGF-β)-induced Xenopus embryos. It plays an important role in the development of mesoderm. Phosphorylation of the c-Myb-related site leads to ubiquitination of c-Myb and degradation of the proteasome. In addition, NLK is also involved in the Notch/Delta signaling pathway and is closely related to the development of the animal mesoderm blood system.

It was found that NLK inhibits the transcriptional activity of the β-catenin/TCF complex by phosphorylating T cell factor (TCF) and inhibits the classical Wnt signal. The Wnt/β-catenin signaling pathway plays an important role in tumor formation, suggesting that NLK, a negative regulator of the Wnt/β-catenin signaling pathway, may be a tumor suppressor. Other studies have shown that NLK acts as a tumor suppressor gene in breast cancer tissues and inhibits tumors by inhibiting the Wnt/βcatenin signal pathway. In the cascade of TAK1-NLK signaling, TGF-β-activated kinase 1 (TAK1) is a downstream agonist of NLK kinase activity, and the TAK1-NLK pathway is regulated negatively. The classical Wnt/β-catenin pathway plays an important role. NLK phosphorylates T cell factor/lymphocyte potentiating factor and inhibits its activity. NLK is able to directly phosphorylate lymphocyte enhancer factor 1/T cytokines (LEF1/TCFs) to block beta-catenin LEF1/TCFs complex binding to DNA. NLK phosphorylation of LEF1/TCFs simultaneously promotes ubiquitination of LEF1/TCFs, leading to degradation of LEF1/TCFs, thereby inhibiting β-catenin-dependent transcription.

Nlk Figure 1. Schematic representation of the proposed signaling pathways for NLK-inhibited Nurr1 expression in PCa cells. (Wang, J., et al. 2016)

NLK and Tumor

The study used immunohistochemistry (IHC) staining to find that NLK was only expressed in the nucleus of ovarian cancer tissue, which was significantly reduced compared with normal ovarian tissue. The down-regulated NLK was not associated with malignant cells, age, cytopathology, residual tumor, ascites, and ascites, but was closely related to clinical stage and pathological grade. In a 5-year follow-up study, abnormally expressed NLK was significantly associated with prognosis in patients. The high overall survival rate of patients with low expression of NLK was significantly lower in patients, suggesting that NLK is one of the indicators for predicting the prognosis of patients with ovarian cancer. Furthermore, in vitro studies have found that NLK plays an important role in the chemotherapy of ovarian cancer. Overexpression of NLK promoted cisplatin-induced apoptosis in ovarian cancer SKOV3 cells and inhibited their growth; inhibition of NLK reversed cisplatin-induced apoptosis and growth of SKOV3 cells.

Studies have confirmed that NLK expression is significantly up-regulated in human hepatocellular carcinoma tissues compared with corresponding normal liver tissues, and significant NLK overexpression in hepatocellular carcinoma occurs. Targeting cleavage of NLK inhibits both cyclin D1 and cyclin-dependent protein kinase 2, thereby inhibiting hepatoma cell growth and cell cycle transition. NLK can be used as a target protein of miRNA, and participates in the process of miRNA regulating tumor cell growth and proliferation.

References:

Wang, J. , Yang, Z. H. , Chen, H. , Li, H. H. , Chen, L. Y. , & Zhu, Z. , et al. (2016). Nemo-like kinase as a negative regulator of nuclear receptor nurr1 gene transcription in prostate cancer. BMC Cancer, 16(1), 257.
Todd, T. W. , Kokubu, H. , Miranda, H. C. , Cortes, C. J. , & Spada, A. R. L. . (2015). Nemo-like kinase is a novel regulator of spinal and bulbar muscular atrophy. eLife, 4, (2015-08-24), 4.
Shawhallgren, G., Chmielarska, M. K., Zarrizi, R., Hellman, U., Karlsson, P., & Helou, K., et al. (2014). Association of nuclear-localized nemo-like kinase with heat-shock protein 27 inhibits apoptosis in human breast cancer cells. Plos One, 9(5), e96506.

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