Aurora Kinase B (AURKB) is a protein kinase, an enzyme that modifies other proteins by adding phosphate groups, a process known as phosphorylation. This action can alter the function of the target protein. AURKB is a fundamental component within cells, playing a significant role in various biological processes.
Understanding Aurora Kinase B
AURKB is a serine/threonine protein kinase. It is encoded by the AURKB gene, located on chromosome 17 in humans. This protein is part of a larger family of enzymes called Aurora kinases, which includes Aurora Kinase A (AURKA) and Aurora Kinase C (AURKC).
Within the cell, AURKB’s location changes throughout the cell cycle, particularly during cell division. It is a component of the chromosomal passenger complex (CPC), a group of proteins that dynamically associate with chromosomes. This complex and AURKB’s specific localization are important for its regulatory functions, ensuring it acts at the right place and time during cellular processes.
AURKB’s Crucial Role in Cell Division
AURKB’s primary function is in the regulation of mitosis, the process of cell division. It orchestrates several events that ensure accurate chromosome segregation and cell splitting. During prophase, AURKB localizes to chromosomes, then moves to the centromeres during prometaphase and metaphase.
One of its key roles involves the phosphorylation of histone H3 on serine 10. This phosphorylation contributes to proper chromosome structure and compaction. Furthermore, AURKB helps correct faulty connections between spindle fibers and kinetochores, which are protein structures on chromosomes, ensuring accurate chromosome alignment before they separate.
As cells progress from metaphase to anaphase, AURKB relocates to the microtubules in the central spindle. It regulates proteins involved in microtubule dynamics, thus influencing spindle formation and function. Finally, AURKB is also involved in cytokinesis, the physical division of the cell into two daughter cells, by localizing to the mid-body during telophase and regulating proteins that manage the cleavage furrow formation.
When AURKB Goes Awry: Implications for Health
When AURKB’s function is disrupted, it can have consequences for cellular health, particularly in the context of disease. Dysregulation of AURKB, whether through overexpression or mutations, can lead to uncontrolled cell growth and genomic instability. These are hallmarks observed in various types of cancer.
Overexpression of AURKB is a common finding in numerous human tumors, including those of the breast, colon, kidney, lung, and prostate. Such elevated levels can result in aneuploidy, a condition where cells have an abnormal number of chromosomes. This chromosomal imbalance contributes to the development and progression of tumors, promoting cell proliferation by inhibiting cell cycle checkpoints and influencing pathways like the AKT/mTOR signaling pathway.
AURKB dysregulation can also contribute to cancer progression by suppressing the activity of tumor suppressor proteins like p53, thereby reducing apoptosis, or programmed cell death. It can also promote the expression of enzymes that degrade the extracellular matrix, facilitating the invasion and spread of cancer cells. The altered expression of AURKB has been observed in various cancers, including retinoblastoma, where its overexpression correlates with tumor invasion.
AURKB as a Therapeutic Target
The understanding of AURKB’s involvement in cancer development has positioned it as a target for drug development. The goal of targeting AURKB in cancer therapy is to inhibit its enzymatic activity, thereby disrupting the uncontrolled proliferation of cancer cells. This approach is part of targeted therapies, which aim to specifically interfere with molecules involved in disease progression.
Many drugs developed to target AURKB are “kinase inhibitors,” designed to block the enzyme’s active site, often by competing with ATP, the molecule AURKB uses for phosphorylation. These small molecule inhibitors aim to prevent AURKB from phosphorylating its substrates, thereby halting abnormal cell division and inducing cell death in cancer cells. Such inhibitors can lead to cell cycle arrest and increased apoptosis in tumor cells, as observed in studies on retinoblastoma.
Both AURKB-selective inhibitors and pan-Aurora inhibitors (which target multiple Aurora kinases) have been developed and are being investigated. Preclinical studies using cell lines and animal models have shown the antitumor properties of these inhibitors. Currently, clinical trials are underway, ranging from Phase I to Phase III, to evaluate the safety and effectiveness of AURKB inhibitors alone or in combination with other cancer treatments.