LKB1, or liver kinase B1, is a fundamental protein in human biology, playing a broad role in maintaining the health and proper functioning of cells throughout the body. Understanding LKB1’s mechanisms provides insights into how our cells manage growth and energy, contributing to overall biological stability.
What is LKB1
LKB1 is a protein kinase, an enzyme that modifies other proteins by adding phosphate groups, a process called phosphorylation. This modification often acts like an on/off switch, regulating the activity of target proteins. The LKB1 protein is encoded by the STK11 gene, found on chromosome 19 in humans.
LKB1 is present in nearly all cell types and tissues throughout the body, with particularly high expression observed in the pancreas, liver, testes, and skeletal muscle. LKB1 acts as a master regulator, influencing multiple cellular pathways necessary for normal cell operation and overall physiological balance.
LKB1’s Central Role in Cell Regulation
LKB1 serves as a central orchestrator of several cellular processes, particularly in metabolism and growth control. A primary function involves activating adenosine monophosphate-activated protein kinase (AMPK), a major energy sensor within cells. When cellular energy levels are low, LKB1 phosphorylates and activates AMPK. This shifts the cell’s metabolism from building molecules to breaking them down for energy, maintaining energy balance and ensuring cells have sufficient fuel.
LKB1 also regulates cell growth and proliferation. By activating AMPK, LKB1 helps suppress cell growth when nutrients are scarce. This ensures that cells do not divide uncontrollably, especially under unfavorable conditions. The LKB1-AMPK pathway also influences the mammalian target of rapamycin complex 1 (mTORC1) signaling, a key regulator of protein synthesis and cell growth. LKB1’s activity can inhibit mTORC1, thereby reducing cell proliferation.
LKB1 plays a role in maintaining cell polarity, the organized structure and orientation of cells. Cell polarity is necessary for tissues to form correctly and for specialized cell functions. LKB1 achieves this by activating a group of 14 other kinases, including AMPK and AMPK-related kinases, contributing to the proper arrangement of cellular components. Loss of LKB1 can lead to disorganized cell polarity, which can facilitate uncontrolled cell growth.
When LKB1 Goes Wrong
Dysfunction of LKB1 has significant consequences, primarily due to its role as a tumor suppressor gene. Tumor suppressor genes code for proteins that normally control cell division, ensuring it only occurs when needed. When LKB1 is mutated or becomes inactive, its ability to regulate cell growth and metabolism is compromised, allowing cells to grow and divide without proper control.
A direct link to LKB1 dysfunction is Peutz-Jeghers Syndrome (PJS), an inherited disorder characterized by the development of benign growths called hamartomatous polyps, predominantly in the gastrointestinal tract, and distinct dark spots on the skin and mucous membranes. Individuals with PJS have germline mutations in the LKB1/STK11 gene, which significantly increases their lifetime risk of developing various cancers, including colorectal, breast, lung, pancreatic, and gastric cancers.
Inactivating mutations in LKB1 are also frequently found in sporadic cancers, meaning those that are not inherited. For instance, LKB1 mutations are common in non-small cell lung cancer, affecting approximately one-third of cases, and are also observed in cervical, breast, intestinal, testicular, and skin cancers. When LKB1 is lost, cells may undergo metabolic reprogramming, increasing processes like glycolysis, which can support rapid cancer cell growth and survival. Loss of functional LKB1 can also lead to resistance to certain cancer therapies.
LKB1 as a Research Target
LKB1 is an important target in scientific research, particularly in cancer biology. Scientists are actively studying LKB1 to understand its complex roles in cellular processes and to identify ways to exploit its dysfunction for therapeutic benefit. The unique vulnerabilities that arise in LKB1-deficient tumors present opportunities for developing new treatment strategies.
A major area of focus is developing targeted therapies for cancers with LKB1 mutations, especially since these tumors often respond poorly to standard chemotherapy and immunotherapy. Researchers are exploring compounds that can activate the LKB1-AMPK pathway, such as metformin and AICAR, which have shown promise in preclinical studies by suppressing tumor development. Other approaches involve identifying “co-vulnerabilities” in LKB1-mutated cancers, meaning pathways that become uniquely susceptible to inhibition when LKB1 is absent. For example, studies have investigated combining FDA-approved drugs like trametinib with other agents to reduce tumor size in LKB1-mutated non-small cell lung cancer.
Despite challenges, such as the complete absence of the LKB1 protein in some mutated tumors making direct targeting difficult, research is progressing. Efforts include understanding how LKB1 loss alters the tumor microenvironment and metabolism, which could reveal new avenues for intervention. Ongoing research aims to translate these scientific insights into more effective clinical treatments for patients with LKB1-deficient cancers.