The STK11 gene, also recognized as Liver Kinase B1 (LKB1), plays a significant role in human biology. This gene provides instructions for creating an enzyme, serine/threonine kinase 11, which acts as a tumor suppressor. The enzyme functions to regulate various cellular processes, helping to maintain normal cell behavior and prevent uncontrolled growth.
The STK11 Gene and Protein
The LKB1 protein is a highly conserved master kinase that regulates cellular metabolism, cell polarity, and growth through a complex signaling network. LKB1 primarily localizes in the nucleus and, to a lesser extent, in the cytosol, though it can also be found in cell membranes and mitochondria during apoptosis.
The LKB1 protein forms a complex with two accessory proteins, STE20-related kinase adaptor (STRAD) and mouse protein 25 (MO25), also known as calcium binding protein 39 (CAB39). This complex formation is essential for LKB1’s activity, as STRAD and MO25 promote a conformational change in LKB1, leading to its active state. LKB1’s functions include regulating cell cycle arrest, apoptosis, and energy metabolism.
STK11 as a Tumor Suppressor
The LKB1 protein achieves this by regulating key cellular pathways, such as the AMP-activated protein kinase (AMPK) pathway. AMPK acts as an energy sensor within the cell, and LKB1 activates it to restore cellular energy balance by promoting processes that generate ATP and inhibiting those that consume it.
LKB1 phosphorylates and activates AMPK and a family of 12 other AMPK-related kinases, which are involved in maintaining cell polarity and metabolism. When STK11 function is lost or impaired, cells can lose their proper orientation and experience deregulated energy metabolism, contributing to uncontrolled cell growth and tumor formation. This loss of function can lead to increased cell motility and invasiveness, enhancing metastatic potential.
Peutz-Jeghers Syndrome and STK11
Germline mutations in the STK11 gene are directly linked to Peutz-Jeghers Syndrome (PJS), an inherited autosomal dominant disorder. Individuals with PJS develop hamartomatous polyps, which are noncancerous growths, primarily in the gastrointestinal tract. These polyps can appear throughout the small intestine, large intestine, and stomach.
PJS is also characterized by distinctive mucocutaneous pigmentation, appearing as dark spots on the lips, inside the mouth, and on the fingers and toes. Individuals with PJS have a significantly increased risk of developing various cancers, including:
- Colorectal cancer
- Pancreatic cancer
- Gastric cancer
- Breast cancer
- Uterine cancer
- Cervical cancer
- Lung cancer
- Gonadal tumors (affecting the ovaries and testes)
STK11 and Other Cancers
Beyond Peutz-Jeghers Syndrome, somatic (acquired) mutations in the STK11 gene are found in various sporadic cancers. These mutations, which are not inherited but occur during a person’s lifetime, impair the function of the LKB1 protein. This contributes to tumor development and progression in distinct cancer types.
STK11 mutations are frequently observed in non-small cell lung cancer (NSCLC), where their presence can influence treatment response and prognosis. They are also identified in pancreatic cancer, cervical cancer, and melanoma. The loss of LKB1 function in these contexts can lead to metabolic reprogramming within cancer cells, supporting tumor growth and metastasis by altering how cells produce and use energy.