ZAK

What is ZAK protein?

ZAK (Sterile Alpha Motif and Leucine Zipper Kinase) is also known as MAP3K20. MAP3K20 gene (mitogen-activated protein kinase kinase kinase 20) is a protein coding gene which situated on the long arm of chromosome 2 at locus 2q31. This gene is a member of the MAPKKK family of signal transduction molecules and encodes a protein with an N-terminal kinase catalytic domain, followed by a leucine zipper motif and a sterile-alpha motif (SAM). This magnesium-binding protein forms homodimers and is located in the cytoplasm. The protein mediates gamma radiation signaling leading to cell cycle arrest and activity of this protein plays a role in cell cycle checkpoint regulation in cells. The protein also has pro-apoptotic activity. The ZAK protein is consisted of 800 amino acids and ZAK molecular weight is approximately 91.2 kDa.

What is the function of ZAK protein?

ZAK protein is a serine/threonine kinase belonging to the mitogen-activated protein kinase kinase kinase (MAP3K) family. It plays a role in a variety of biological processes, including apoptosis, cell cycle control, tumorigenesis and development, cardiac hypertrophy, and response to stress. ZAK protein is involved in the regulation of cellular stress responses by activating downstream mitogen-activated protein kinase (MAPK) signaling pathways, such as c-Jun N-terminal kinase (JNK) and p38 MAPK. In addition, ZAK is involved in epithelial-mesenchymal transformation, a process that is critical in embryonic development, tissue repair, organ fibrosis, and cancer progression. In cancer, increased expression of ZAK is associated with poor prognosis, particularly in patients with breast cancer. ZAK may also influence metabolic changes during obesity and aging by regulating metabolism.

Fig1. Fisetin upregulates ZAKα expression to turn on the Hippo pathway and increases JNK/ERK activation in AP-1 dependent manner. (Chien-Yao Fu, 2019)

ZAK related signaling pathway

ZAK is involved in regulating cellular stress response and cell cycle progression by activating downstream mitogen-activated protein kinase (MAPK) signaling pathways, such as c-Jun N-terminal kinase (JNK) and p38 MAPK. In addition, ZAK plays a role in regulating apoptosis, tumor cell proliferation and migration, and adaptation in the tumor microenvironment. ZAK plays a key role in signaling pathways in cancer development, particularly during epithelial-mesenchymal transition. During EMT, ZAK induces the expression of mesenchymal markers, such as vimentin, fibronectin, and N-cadherin, while inhibiting the expression of epithelial markers, such as E-cadherin. ZAK may also promote EMT by activating transcription factors, such as ZEB1.

ZAK related diseases

The ZAK protein has been implicated in a variety of diseases, especially in cancer and kidney disease. In cancer progression, ZAK increases tumor aggressiveness and metastatic ability by promoting epithelial-mesenchymal transformation. Its increased expression in a variety of cancers is associated with poor prognosis, particularly in patients with breast cancer. In addition, ZAK also plays a role in tumor cells' resistance to nutrient deprivation and chemotherapy drugs, possibly by regulating signaling pathways associated with EMT. In kidney disease, ZAK expression is associated with the degree of renal fibrosis and decreased kidney function in patients with chronic kidney disease. Studies have shown that ZAK expression is increased in renal tubular epithelial cells and is associated with renal fibrosis and inflammatory response.

Bioapplications of ZAK

ZAK can be used as a potential target for cancer therapy, and by inhibiting the activity or expression of ZAK, it may help to inhibit the proliferation and metastasis of tumor cells, thereby improving the therapeutic effect. ZAK's role in renal fibrosis makes it a potential target for the treatment of kidney disease. The kinase activity of ZAK makes it an important target for drug development. The variation in the expression level of ZAK in different disease states makes it a potential biomarker for disease. ZAK's role in cellular stress responses makes it an important tool for studying how cells respond to external stimuli, such as ultraviolet radiation.

Case Study 1: Chien-Yao Fu, 2020

Despite improvements in surgery and chemotherapy for osteosarcoma (OS), outcomes are still unfavorable. The compound 3-hydroxylflavone, which controls ROS levels, has shown potential in curbing OS cell growth, but its detailed mechanisms are unknown. This study explores how 3-Hydroxy-2-phenylchromone (3-HF) affects OS using human HOS cells. Results showed that 3-HF boosts ZAK protein expression, promoting apoptosis. Specifically, 3-HF activates the ZAKβ isoform, which triggers ZAKα, leading to increased cancer cell death.

Fig1. Western blot analysis of the expression of Zipper sterile-alpha-motif kinase (ZAK).

Fig2. Role of ZAK in 3-HF-induced apoptosis in HOS cells.

Case Study 2: Linna Li, 2018

ZAK, a kinase, can either promote or inhibit cell growth and is a key regulator in epithelial-mesenchymal transition (EMT). This screening identified ZAK as a significant factor in EMT, where its overexpression in epithelial cells induces EMT and resistance to apoptosis. In contrast, ZAK deficiency in mesenchymal cancer cells lessens EMT traits, enhances drug sensitivity, and reduces bone metastasis risk, with minimal effect on tumor growth. We found that ZAK's role in EMT involves ZEB1 activation and ESRPs repression, leading to a shift in CD44 isoforms. Importantly, high ZAK levels correlate with poor survival rates across various cancers, and in breast cancer, it's a strong independent predictor of worse outcomes, potentially enhancing the prognostic value of other clinical markers by up to 21%.

Fig3. ZAK-induced alterations of ZEB1 and downstream genes in HMLE, PC3 and HEK293T cells.

Fig4. Immunofluorescence staining patterns of vimentin and E-cadherin in MDA-MB-231 cells expressing shCrtl or shZAKs.

ZAK has several biochemical functions, for example, ATP binding,MAP kinase kinase kinase activity,magnesium ion binding. Some of the functions are cooperated with other proteins, some of the functions could acted by ZAK itself. We selected most functions ZAK had, and list some proteins which have the same functions with ZAK. You can find most of the proteins on our site.

ZAK has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with ZAK here. Most of them are supplied by our site. Hope this information will be useful for your research of ZAK.