Sandbox 465
From Proteopedia
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| - | <Structure load='2wtk' size='350' frame='true' align='right' caption=' | + | <Structure load='2wtk' size='350' frame='true' align='right' caption=' Serine/Threonine Kinase 11 complexed with STRADA and MO25' scene='Insert optional scene name here' /> |
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| - | == | + | == Function == |
| - | STK11 | + | |
| + | 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 STRADA and the protein MO25. Both STRADA and MO25 allosterically promote the activation of STK11, which is also stabilized by MO25 interacting with the STK11 activation loop. The STK11 alpha helix is rotated into a closed conformation, conserving salt bridge between <scene name='72/728131/Lys/2'>lys78</scene> and <scene name='72/728131/Glu/3'>glu98</scene> . This is where the active conformation is formed <ref> PMID: 19892943 </ref>. STK11 facilitates cell cycle arrest through induction of cyclin-dependent kinase inhibitor p21WAF1, through a p53-dependent process <ref name="loss"> PMID: 12861065</ref>. | ||
| + | P21 inhibits apoptosis and may promote cell proliferation in some tumors <ref> PMID: 19449443 </ref>. STK11 also interacts with brahma-related gene-1 ([[Brg1]]), an ATPase that is associated with SWI/SNF chromatin-remodeling complexes. Exogenous express of brg1 is able to induce cell cycle arrest and 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 <ref name="loss" />. | ||
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== Location == | == 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 | + | 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 <ref> PMID: 9428765 </ref>. |
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| - | == | + | == Structure == |
| - | + | STK11 has a molecular mass of approximately 50kDa and is the catalytically active unit of a heterotrimeric complex with STE20-related adaptor (STRAD) and mouse protein 25 (MO25). STRAD, 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 STRAD, and as a result enhances the kinase activity of STK11 <ref> | |
| + | STK11. Genetics Home Reference. National Library of Medicine </ref>. STK11 has a <scene name='72/728131/Atp_binding_site/1'>ATP binding site</scene> located at Lys78, a basic amino acid, and a <scene name='72/728131/Nucleotide_binding_site/1'>nucleotide binding site</scene> (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 <scene name='72/728131/Active_site_1/1'>active site</scene> at Asp176, which serves as a proton acceptor <ref> Gan RY, Li HB. Recent Progress on Liver Kinase B1 (LKB1): Expression, Regulation, Downstream Signaling and Cancer Suppressive Function. International Journal of Molecular Science. 2014 Sep; 15(9):16698-16718. </ref>. | ||
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== Disease == | == Disease == | ||
| - | The function of the STK11 is to suppress tumors. A mutation in this protein increases the risk of cancer and carcinomas | + | 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). <ref name="PJ"> PMID: 9425897</ref>, particularly p21WAF1 <ref name="loss" />. CDKN1A regulates cell development during the G1 and S phase of interphase and activates cyclin-dependent kinase 2 to regulate apoptosis <ref> PMID: 25329316 </ref>. 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 <ref name="PJ" />. |
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| - | This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes. | ||
== References == | == References == | ||
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Current revision
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Contents |
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 STRADA and the protein MO25. Both STRADA and MO25 allosterically promote the activation of STK11, which is also stabilized by MO25 interacting with the STK11 activation loop. The STK11 alpha helix is rotated into a closed conformation, conserving salt bridge between and . This is where the active conformation is formed [1]. STK11 facilitates cell cycle arrest through induction of cyclin-dependent kinase inhibitor p21WAF1, through a p53-dependent process [2]. P21 inhibits apoptosis and may promote cell proliferation in some tumors [3]. STK11 also interacts with brahma-related gene-1 (Brg1), an ATPase that is associated with SWI/SNF chromatin-remodeling complexes. Exogenous express of brg1 is able to induce cell cycle arrest and 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 STE20-related adaptor (STRAD) and mouse protein 25 (MO25). STRAD, 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 STRAD, and as a result enhances the kinase activity of STK11 [5]. STK11 has a located at Lys78, a basic amino acid, and a (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 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].
References
- ↑ Zeqiraj E, Filippi BM, Deak M, Alessi DR, van Aalten DM. Structure of the LKB1-STRAD-MO25 Complex Reveals an Allosteric Mechanism of Kinase Activation. Science. 2009 Nov 5. PMID:19892943
- ↑ 2.0 2.1 2.2 Sahin F, Maitra A, Argani P, Sato N, Maehara N, Montgomery E, Goggins M, Hruban RH, Su GH. Loss of Stk11/Lkb1 expression in pancreatic and biliary neoplasms. Mod Pathol. 2003 Jul;16(7):686-91. PMID:12861065 doi:http://dx.doi.org/10.1097/01.MP.0000075645.97329.86
- ↑ Gartel AL. p21(WAF1/CIP1) and cancer: a shifting paradigm? Biofactors. 2009 Mar-Apr;35(2):161-4. doi: 10.1002/biof.26. PMID:19449443 doi:http://dx.doi.org/10.1002/biof.26
- ↑ Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Loukola A, Bignell G, Warren W, Aminoff M, Hoglund P, Jarvinen H, Kristo P, Pelin K, Ridanpaa M, Salovaara R, Toro T, Bodmer W, Olschwang S, Olsen AS, Stratton MR, de la Chapelle A, Aaltonen LA. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature. 1998 Jan 8;391(6663):184-7. PMID:9428765 doi:10.1038/34432
- ↑ STK11. Genetics Home Reference. National Library of Medicine
- ↑ Gan RY, Li HB. Recent Progress on Liver Kinase B1 (LKB1): Expression, Regulation, Downstream Signaling and Cancer Suppressive Function. International Journal of Molecular Science. 2014 Sep; 15(9):16698-16718.
- ↑ 7.0 7.1 Jenne DE, Reimann H, Nezu J, Friedel W, Loff S, Jeschke R, Muller O, Back W, Zimmer M. Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet. 1998 Jan;18(1):38-43. PMID:9425897 doi:10.1038/ng0198-38
- ↑ Esteve-Puig R, Gil R, Gonzalez-Sanchez E, Bech-Serra JJ, Grueso J, Hernandez-Losa J, Moline T, Canals F, Ferrer B, Cortes J, Bastian B, Ramon Y Cajal S, Martin-Caballero J, Flores JM, Vivancos A, Garcia-Patos V, Recio JA. A mouse model uncovers LKB1 as an UVB-induced DNA damage sensor mediating CDKN1A (p21WAF1/CIP1) degradation. PLoS Genet. 2014 Oct 16;10(10):e1004721. doi: 10.1371/journal.pgen.1004721., eCollection 2014 Oct. PMID:25329316 doi:http://dx.doi.org/10.1371/journal.pgen.1004721
