1. Growths in Your Colon Aren’t Fun, Get Yourself Some LKB1! Abstract Billions of dollars are being poured into the research of cancer, the National Cancer Institute alone spends $4.9 Billion every year. Liver Kinase B1 (LKB1) stands out as one important protein that regulates cell metabolism, cell division, and therefore, cancerous growth. LKB1 is a key regulator of cell metabolism and cell division by acting as a tumor suppressor by turning on other proteins that suppress tumor growth. Human mutations in LKB1 causes the disease Peutz-Jeghers syndrome, which results in benign tumor-like growth called polyps in the intestine and a 50% chance of developing cancer by the age of 50. When cell energy, ATP, is low LKB1 will be activated. Active LKB1 regulates the activity of adenosine monophosphate-activated protein kinase (AMPK). LKB1 directly activates AMPK by adding a phosphate group to Thr-172. AMPK activity increases the production of ATP by activating glycolysis and fatty acid oxidation. AMPK can also decrease the amount of energy needed by the cell by inhibiting protein synthesis and cell growth. Both of these processes play a role in cancer development. Drugs like Metformin, a successful diabetic drug, are thought to activate LKB1. Through the activation of AMPK to cease cancerous growth, and with the whole cascade of proteins ceases cancerous growth. LKB1 Mutations and Consequences Peutz-Jeghers syndrome is when benign polyps are present inside the intestines. Patients with Peutz-Jeghers syndrome are prone to colon and rectal cancers as well as a wide variety of other cancers. All cancers, such as those listed, develop when cells rapidly divide in an area, and divide and grow out of control. This growth is called a tumor, and is quite dangerous. The reason these develop is because the cell decides to create proteins and other macromolecules, anabolic pathways, instead of breaking them down to create ATP, catabolic pathways, and the created macromolecules are used for creating new cells. Liver kinase B1 (LKB1), controls which pathway the cell is undergoing, and when active, it makes the cell go through catabolic pathways by phosphorylating 5' adenosine monophosphate- activated protein kinase (AMPK). LKB1 in Mouse Embryos Figure A shows the development of the aorta in both a LKB1 knockout mouse, (right), and a wildtype mouse, (left). The mutated aorta of the knockout mouse is smaller in diameter. Figure B shows the entire embryo, and the arrow points to where the aorta is discontinuous in the knockout mouse (right), and the corresponding area in the wildtype mouse, (left). Figure C shows the tissue of the embryo that will develop into the brain. In the knockout mouse, (right), the mesenchyme layer is not fully developed, as displayed by the asterisks. Metformin Activating ATM Metformin activates Ataxia Telangiectasia Mutated (ATM) which is a serine/threonine protein kinase responsible for the phosphorlation Liver Kinase B1 (LKB1) It is supposed to be activated by DNA double-strand breaks however sometimes they do not function accordingly The activation of ATM and the phosphorlation of LKB1 guides the LKB1 out of the nucleus and into the cytosol Adenosine-monophosphate Activated Kinase (AMPK) is abundant in the cytosol and that is where LKB1 is able to phosphorlate AMPK and continue the cycle Phosphorylated LKB1 Above is an image of two cells, both with LKB1 mutation resulting in the lack of Adenosine-monophosphate Activated Kinase (AMPK) phosphorylation. The one with Metformin results in more LKB1 and AMPK interaction and thus AMPK phosphorylation versus the control. Metformin, a popular anti diabetic drug, activates AMPK by extracting Live Kinase B1 out from the nucleus and into the cytoplasm where AMPK is generally locates. It does this by phosphorylating LKB1 at Ser428 which then helps LKB1 export from the nucleus and meet with AMPK in the cytoplasm, hence phosphorylating AMPK and continuing the natural cycle. Liver Kinase B1 has vital functions inside the cell. It is clear that the proper activation of LKB1 results in the control over the proliferation, cellular metabolism, and cellular integrity of the cell. As a kinase its sole purpose is to phosphorlate making it a stepping stone inside of an important cellular cycle. This cellular cycle is a broad cycle which acts as a check point for the cell. Without this checkpoint the cell would be left helpless in managing its most important components. This would ultimately disrupt the overall homeostasis of the cell and most importantly, if not targeted by apoptosis, have the ability to turn cancerous. Functions of LKB1 LKB1 works as a complex of three parts: LKB1, the psuedokinase STRAD, and MO25. When LKB1 is phosporylated, it in turn activates AMPK. AMPK also is activated by low blood oxygen, as well as low blood glucose. After AMPK is activated, it either turns on anabolic or catabolic pathways. One of these is glucose metabolism. Therefore, if LKB1 is dysfunctional, there could be problems with diabetes. There are drugs like Metformin that activate LKB1 indirectly in order to help those with diabetes. AMPK also regulates cell polarity and cell growth. If either of these is not functioning properly, cancers can develop from cells rapidly dividing out of control, such as colon cancer. This growth can cause mutations and defective tissues all around the body, notably in the vascular system. SMART Teams are supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant Number 8UL1TR000055. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Citations Shaw, R. (2011). The cancer connection. Drugs, diabetes and cancer, 470(338). Xie, Z., Dong, Y., Scholtz, R., Neumann, D., & Zou, M. (2008). Phosporylation of lkb1 at serine 428 by protein kinase c is required for metformin-enchanced activation of the amp-activated protein kinase in endothelial cells. Circulation,117, 952-962. Ylikorkala, A., Rossi, D. J., Korsisaali, N., Luukko, K., Alitalo, K., Henkemeyer, M., & Makela, T. P. (2001). Vascular abnormalities and deregulation of vegf in lkb1-deficient mice. Sciencemag, 293, 1323-1326. Zhao, R., & Xu, Z. (2014). The biological functions of lkb1.Targeting the LKB1 Tumor supressor, 32-52. Acknowledgements We would like to thank Dr. Stephanie Cossette for continuing to help and support us through the process of learning and presenting information about molecular biology. Not only do we now know the specific information, but because of her efforts, we got a glimpse of the work researchers do daily, and the work that goes into it.