STK11

Function

Serine-threonine kinase 11 (STK11) is a tumor suppressor gene that plays an important role in regulating cell growth, cell polarity, and apoptosis. It controls the activity of adenine monophosphate-activated protein kinase (AMPK). STK11 is regulated by the pseudokinase STE20-related adaptor alpha (STRADA) and the mouse protein 25 (MO25). Both STRADA and MO25 allosterically promote the activation of STK11. In addition to activating STK11, MO25 stabilizes STK11 though interacting with the activation loop. The alpha helix is rotated into a closed conformation, conserving the salt bridge between lys78 and glu98. This is where the active conformation is formed ^[1]. STK11 facilitates cell cycle arrest through induction of a cyclin-dependent kinase inhibitor, p21WAF1, through a p53-dependent process to prevent cancer formation ^[2]. Cyclin-dependent kinase inhibitors like p21WAF1 function as a tumor suppressor gene that inhibits apoptosis and may promote cell proliferation in some tumors ^[3]. The gene p21WAF1is also critical for regulating proper cell division. STK11 also interacts with brahma-related gene-1 (Brg1), an ATPase that is associated with SWI/SNF chromatin-remodeling complexes. Exogenous expression of brg1 is able to induce cell cycle arrest thus resulting in a loss of cell power of division and growth in a retinoblastoma-dependent fashion. The tumor suppression function of STK11 lies within its ability to affect the cell cycle proliferation ^[2].

Location

The STK11 gene is located on chromosome 19 on the p arm of the chromosome, also known as the short arm. The exact location is between base pair 1,205,799 and 1,228,435. Location is found in both the nucleus and the cytoplasm. In humans, when STK11 is over expressed it is mostly located in the nucleus, having limited amounts in the cytoplasm. When a cell is undergoing apoptosis, STK11 translocates into the mitochondria. STK11 is mostly expressed in the seminiferous tubules of the testes, showing higher expression in the fetal tissues than in adult tissues ^[4].

Structure

STK11 has a molecular mass of approximately 50kDa and is the catalytically active unit of a heterotrimeric complex with STRADA and MO25. STRADA, a pseudokinase, induces a conformational change in STK11 to form the catalytically active state which transports STK11 from the nucleus to the cytoplasm. MO25, a scaffold protein, strengthens the interaction between STK11 and STRADA, and as a result enhances the kinase activity of STK11 ^[5]. STK11 has a ATP binding site located at Lys78, a basic amino acid, and a nucleotide binding site (9 residues) consisting of hydrophobic amino acids (such as Gly, Leu, and Val), hydrophilic amino acids (such as Ser and Tyr), a basic amino acid (Lys), and an acidic amino acid (Glu). STK11 also has an active site at Asp176, which serves as a proton acceptor ^[6].

Disease

The function of the STK11 gene is to suppress tumors. A mutation in this protein increases the risk of cancer and carcinomas (cancer arising from the epithelial tissue of internal organs primarily in the gastrointestinal (GI) tract). Individuals with this germline mutation are diagnosed with Peutz-Jeghers Syndrome (PJS), an autosomal dominant mutation caused by a disruption of the kinase domain. This is due to improper DNA repair mechanisms and resistance to apoptosis which are both associated with an accumulation of cyclin-dependent kinase inhibitor 1A (CDKN1A). ^[7], particularly p21WAF1 ^[2]. CDKN1A regulates cell development during the G1 and S phase of interphase and activates cyclin-dependent kinase 2 to regulate apoptosis ^[8]. Therefore, a mutation in STK11 leads to CDKN1A malfunction resulting in uncontrolled growth. In addition to cancerous growth, PJS is also characterized by the growth of hamartomatous polyps in the GI tract, neoplasm, and discoloration of the skin and mouth ^[7].