MELK

Official Full Name

maternal embryonic leucine zipper kinase

Organism

Homo sapiens

GeneID

9833

Background

Enables calcium ion binding activity; non-membrane spanning protein tyrosine kinase activity; and protein serine/threonine kinase activity. Involved in apoptotic process; cell population proliferation; and protein autophosphorylation. Located in cell cortex and plasma membrane. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

HPK38;

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Detailed Information

Recent Researches

MELK is located on chromosome 9p13.2 with a total length of 2501 bp, and the encoded protein is composed of 651 amino acid residues. The structure of MELK is highly conserved and consists of N-terminal Ser/Thr kinase region, an adjacent ubiquitination-related (UBA) region and a C-terminal regulatory region. The C regulatory region contains a TP enriched region and a kinase related region 1 (KA1). The TP enrichment region contains multiple phosphorylation sites, where MELK must undergo specific Thr phosphorylation to inhibit splicing assembly; the KA1 region is associated with membrane junction of some AMPK-related kinases, which may inhibit MELK activity. AMPK is the only kinase family with UBA domain. The classical UBA domain can bind to ubiquitin and prevent the degradation of ubiquitin-dependent proteins. However, the AMPK related kinase UBA region is nonclassical and lacks ubiquitination activity. MELK activation is dependent on the phosphorylation of Thr167, Ser/Thr residues, UBA and TP enrichment regions. Phosphorylation of Thr167 and Ser171 is necessary for MELK activation. MELK is also a Ca²⁺ binding protein. Physiological dose of Ca²⁺ can inhibit the activity of MELK.

MELK protein has a leucine zipper structure, which has a core sequence of about 30 amino acid residues in the domain where DNA is bound. The N-terminal of MELK protein is rich in alkaline amino acids, forming a DNA binding surface. Every six amino acid residues regularly appear one leucine residue, which can form amphoteric alpha-spiral. One side of the helix is mainly charged amino acid residues that are hydrophilic, while the other side is a row of leucine, which is hydrophobic. This structural sequence is found in many DNA-binding proteins and is thought to be associated with protein-DNA and protein-protein interactions.

Unlike other members of the MARK kinase family, MELK is not involved in metabolic regulation, but in other cellular processes such as cell proliferation, apoptosis, cell cycle regulation, precursor splicing of mRNA, stem cell and embryonic cell development. In addition, MELK interacts with multiple proteins and participates in multiple stages of tumor formation. Current studies on MELK function mainly focus on cell cycle regulation, embryonic development regulation and the role in tumor formation. In addition, MELK interacts with a variety of proteins by direct binding and phosphorylation to maintain the balance of proliferation and apoptosis during tissue development.

The MELK gene has the characteristics of oncogene. MELK is highly expressed in malignant epithelial tumors from digestive tract, lung, ovary, breast, skin and other tissues. The expression of MELK is correlated with malignancy, prognosis and drug resistance. Knocking out MELK gene can inhibit the growth of tumor cells in vivo and in vitro. More importantly, the characteristics of MELK embryonic expression and kinase activity may serve as a potential target gene for intervention in cancer stem cell therapy strategies.

MELK participates in the proliferation of neural progenitor cells and is closely related to multiple brain tumors. Therefore, MELK can be used as a cell marker of pluripotent neural progenitor cells (MNP). Overexpression of MELK can enhance the formation of MNP neurospheres, while down-regulation of MELK can block the transformation of GFAP-positive MNP into GFAP-negative MNP and decrease the expression of Bmyb. These suggest that MELK is necessary for the proliferation and differentiation of neural progenitor cells. The expression of MELK is positively correlated with the malignancy of astrocytoma. The down-regulation of MELK expression in malignant astrocytoma can reduce non-anchorage-dependent growth. MELK is closely related to the occurrence of breast cancer. It was found that the increased expression of MELK in breast cancer tissues is also associated with poor prognosis, possibly because MELK participates in Bcl-G signaling pathway and plays an anti-apoptosis role in breast cancer.

MELK is associated with chemoradiation resistance in rectal cancer. The resistance to 5-FU is associated with the expression of MELK. It was found that the expression of MELK in SNU-503 cell line increases after radiotherapy or 5-FU treatment, while the cell line pretreated with siRNA also receives radiotherapy or 5-FU treatment, and the cell proliferation is significantly decreased. MELK may play an anti-apoptotic role in this process.

In conclusion, MELK exerts a variety of biological functions through protein-protein interactions, and its high expression in various tumor tissues suggests that MELK plays an important role in tumor formation. Although the function and mechanism of MELK are still unknown, it is certain that MELK plays an important role in tumorigenesis and can be used as a potential target for the treatment of tumors.

References:

Jiang Pengfei, et al. Maternal embryonic leucine zipper kinase (MELK): A novel regulator in cell cycle control, embryonic development, and cancer [J]. International Journal of Molecular Sciences, 2013, (11): 21551-21560. DOI:10.3390/ijms141121551.
Pang Li, et al. MELK and its progress in cancer research [J]. Biotechnology Communication, 2016, (1): 128-132. DOI: 10.3969/j.issn.1009-0002.2016.01.031.
Gu,C. et al. Tumor-specific activation of the C-JUN/MELK pathway regulates glioma stem cell growth in a p53-dependent manner [J]. Stem Cells, 2013, (5): 870-881.

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