Maternal embryonic leucine zipper kinase (MELK) is a unique member of the sucrose non-fermented 1/AMP activated protein kinase (Snf1 / AMPK) family and is a cycle-dependent kinase. Unlike other members of the family, MELK is not involved in the regulation of cell survival under metabolic stress, but is more involved in the cell cycle, cell proliferation, tumorigenesis, and apoptosis. The expression of MELK is elevated in many human tumors, which is closely related to the prognosis of tumors. MELK is abnormally activated in tumor stem cells, allowing tumor cells to grow, invade, and migrate. Therefore, MELK can be an important target for tumor treatment.
Introductions
MELK is a unique member of the Snf1/AMPK kinase family and is a conserved cycle-dependent kinase. Unlike other members of the family, MELK is not involved in cell energy metabolism balance, but more involved in cell cycle regulation, cell proliferation, tumorigenesis, and apoptosis. MELK is widely expressed and has strong tissue specificity. It is highly expressed in tissues with strong ability to divide and self-renew, such as epithelial tissue, hematopoietic tissue, embryonic tissue, undifferentiated tumor tissue, etc. Kidney and other tissues and organs are not expressed or the content is very small. MELK has increased expression in various human tumors such as brain astrocytoma, glioblastoma, breast cancer, and melanoma. It is speculated that MELK can promote tumor formation. In addition, high MELK expression is associated with poor patient prognosis. MELK is abnormally activated in tumor stem cells, allowing tumor cells to grow, invade, and migrate; meanwhile, MELK is also expressed in normal progenitor cells, suggesting that abnormal regulation of MELK may lead to tumor formation in different cell types.
Structures
The structure of MELK hMELK is located on chromosome 9p13.2 and has a total length of 2501 bp. The encoded protein consists of 651 amino acid residues. The structure of MELK is highly conserved and consists of an N-terminal Ser/Thr kinase region and an adjacent ubiquitination-related (UBA) region and a C-terminal regulatory region. The C-terminal regulatory region contains a TP-rich region and a kinase-associated region 1 (KA1). The C-terminal regulatory region is related to the self-inhibition of MELK kinase activity; the TP-rich region contains multiple phosphorylation sites, and specific Thr phosphorylation of this region is necessary for MELK to inhibit spliceosome assembly; the KA1 region is associated with some AMPK-related kinases Membrane connection is related and may have an inhibitory effect on MELK activity. The AMPK kinase family is the only kinase family with a UBA region. The classic UBA region can bind to ubiquitin to prevent ubiquitin-dependent proteins from being degraded. However, the UBA region of the AMPK-related kinase adopts a nonclassical structure and lacks ubiquitination activity. LKB1 acts on the UBA region, activates AMPK-related kinases and phosphorylates the highly conserved Thr site. MELK is the only kinase in this family that is not activated by LKB1. Phosphorylation of Thr167 and Ser171 is necessary for MELK activation. MELK is also a Ca2+ binding protein, and physiological doses of Ca2+ can inhibit MELK activity.
Functions
Unlike other members of the MARK kinase family, MELK is not involved in metabolic regulation, but is involved in other cellular processes such as cell proliferation, apoptosis, cell cycle regulation, mRNA precursor splicing, stem cell and embryonic cell development. In addition, MELK interacts with multiple proteins and participates in multiple stages of tumor formation. Current research on MELK function has focused on cell cycle regulation, embryonic development regulation, and its role in tumor formation. MELK is involved in cell cycle regulation. MELK expression is obviously cell cycle-dependent. Phosphorylated MELK can be detected at the G2 phase of mitosis until it reaches its peak at the end of mitosis. When the cell division phase is blocked, MELK detection is extremely low, and MELK gene silencing can be speculated to cause G2-M transformed cell accumulation to play an important role in cell cycle regulation, which may be related to MELK activation of CDC25B-related phosphorylase. Some researchers speculate that MELK is necessary for cells to pass the G2-M checkpoint, but once it passes the checkpoint, its effect will be suppressed. Further research found that MELK protein is tightly regulated in tumor and normal tissue proliferating cells.
Conclusions
MELK exerts a variety of biological functions through protein-protein interactions, and its high expression in various tumor tissues suggests that it plays an important role in tumor formation. However, the exact function of MELK in tumor formation has not been fully revealed, and many of its molecular mechanisms are still unknown. Further research needs to clarify the mechanism through which MELK participates in tumor formation. Although the function and mechanism of MELK are still unknown, it is certain that it plays an important role in tumor formation and can be used as a potential target for treating tumors.
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