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Burke, J. E., Triscott, J., Emerling, B. M., Hammond, G. R. V. (2022). Beyond PI3Ks: targeting phosphoinositide kinases in disease. Nature Reviews.
Lipid phosphoinositides are an important part of the cell’s membrane, the wall that encapsulates the cell’s inner parts. They play a large part in regulating processes in the cell, essentially acting like a person turning on or off a light, but in cellular function terms. Mainly, it regulates phosphoinositide kinases, which are enzymes (proteins that speed up chemical reactions) involved in cell growth, differentiation (which is when cells change to a specialized type, like a blood cell), proliferation (increase in numbering), and survival. Current research shows it is possible to use lipid phosphoinositides to treat cancer, viral infections, neurodegenerative diseases (when cells of the nervous system no longer work), developmental disorders, diabetes, and inflammatory diseases.
The first class of phosphoinositide kinases are called PI3Ks. In cancer, it is often these enzymes that are mutated. Thus, it is crucial that there is not too much or too little presence of these enzymes in the cell. When they are activated too much, it is called “hyperactivation,” which leads to a variety of problems, such as too much cell division, cell mutations, unregulated production of proteins, organelle (components of the cell) defects, and cell membrane rigidity (which impairs function and protection). However, their inhibition can cause deficiencies for the immune system and developmental disorders because cells are not growing or differentiating at a high enough rate. Scientific research has discovered that regulating PI3Ks to be at that right amount of on/off is a useful treatment for cancers such as blood cancers and tumor-based cancer. Unfortunately, these treatments have significant side effects such as hyperglycemia, which is when blood sugar levels spike. New ongoing research is attempting to find methods to specifically target mutant cancerous PI3Ks instead of all of them, which would decrease negative side effects.
Another type of phosphoinositide kinase is called PIKfyve, the regulation of which could be a promising treatment for neurodegenerative diseases. For example, in the rare disorder type 4B Charcot-Marie-Tooth disease, a PIKfyve mutation was devastating to the nervous system, leading to symptoms like leg paralysis and foot deformities. By inhibiting these mutated kinases from continuing to expand in number, it is possible that the disease could be cured at its root. Through experimental trials, this has already shown promise in mice, who have gained greater nerve control and fewer abnormalities through the regulation of mutated kinases. Overall, the regulation of PIKfyve has the potential to help people with Alzheimer’s disease, Parkinson’s disease, and dementia. However, more research needs to be done to consider the long term effects and toxicity of the treatment.
Finally, PI5P4Kβ is another type of phosphoinositide kinase that holds potential for a cure for type 2 diabetes. By using inhibitors to turn off this kinase, insulin sensitivity increases, which can ultimately decrease blood sugar levels. However, the complexity of the role of PI5P4Kβ in insulin signaling pathways—which are processes that occur in cells to regulate the levels of glucose—may potentially influence how effective any inhibitors introduced to the cell would be. Additionally, all current research has been done on diabetic rats and has not yet expanded to humans. Thus, more research needs to be conducted to fully understand the capabilities of inhibitors in treating diabetes.
Overall, using phosphoinositide kinase inhibitors are one of scientific researchers’ next steps to combat some of the biggest diseases plaguing humans today. Although the treatment methods and practical effects of these inhibitors are not yet fully known, past research seems promising and more research is ongoing to explore the vast possibilities inhibitors offer.
Summarized by Jeannine Yu
References:
“Charcot-Marie-Tooth Disease.” National Institute of Neurological Disorders and Stroke, www.ninds.nih.gov/health-information/disorders/charcot-marie-tooth-disease.
Fabbro, Doriano, et al. “Ten Things You Should Know about Protein Kinases: Iuphar Review 14.” British Journal of Pharmacology, June 2015, www.ncbi.nlm.nih.gov/pmc/articles/PMC4439867/.
“Hyperglycemia (High Blood Glucose).” Hyperglycemia (High Blood Glucose) | ADA, diabetes.org/healthy-living/medication-treatments/blood-glucose-testing-and-control/hyperglycemia#:~:text=Hyperglycemia%20is%20the%20technical%20term,can%27t%20use%20insulin%20properly.
“NCI Dictionary of Cancer Terms.” National Cancer Institute, www.cancer.gov/publications/dictionaries/cancer-terms/def/cell-differentiation.
“Peripheral Neuropathy.” National Institute of Neurological Disorders and Stroke, www.ninds.nih.gov/health-information/disorders/peripheral-neuropathy#:~:text=What%20is%20peripheral%20neuropathy%3F,other%20parts%20of%20the%20body.
“PIKFYVE Phosphoinositide Kinase, FYVE-Type Zinc Finger Containing [Homo Sapiens (Human)] - Gene - NCBI.” National Center for Biotechnology Information, www.ncbi.nlm.nih.gov/gene/200576#:~:text=PIKfyve%20regulates%20endomembrane%20homeostasis%20and,carrier%20vesicles%20from%20early%20endosomes.
Sims-Robinson, Catrina. “Insulin Signaling.” Insulin Signaling - an Overview | ScienceDirect Topics, 2015, www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/insulin-signaling#:~:text=Insulin%20signaling%20is%20initiated%20through,31%2D4).
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