Stathmin, also known as metablastin and oncoprotein 18 is a protein that in humans is encoded by the STMN1gene.
Stathmin is a highly conserved 17 kDaprotein that is crucial for the regulation of the cell cytoskeleton. Changes in the cytoskeleton are important because the cytoskeleton is a scaffold required for many cellular processes, such as cytoplasmic organization, cell division and cell motility.[1] More specifically, stathmin is crucial in regulating the cell cycle.[2] It is found solely in eukaryotes.
Its function as an important regulatory protein of microtubule dynamics has been well-characterized.[3] Eukaryotic microtubules are one of three major components of the cell’s cytoskeleton. They are highly dynamic structures that continuously alternate between assembly and disassembly. Stathmin performs an important function in regulating rapid microtubule remodeling of the cytoskeleton in response to the cell’s needs. Microtubules are cylindrical polymers of α,β-tubulin. Their assembly is in part determined by the concentration of free tubulin in the cytoplasm.[4]
At low concentrations of free tubulin, the growth rate at the microtubule ends is slowed and results in an increased rate of depolymerization (disassembly).[3][5]
Stathmin, and the related proteins SCG10 and XB3, contain a N-terminal domain (XB3 contains an additional N-terminal hydrophobic region), a 78 amino acidcoiled-coil region, and a short C-terminal domain.
Function
The function of Stathmin is to regulate the cytoskeleton of the cell. The cytoskeleton is made up of long hollow cylinders named microtubules. These microtubules are made up of alpha and beta tubulinheterodimers. The changes in cytoskeleton are known as microtubule dynamics; the addition of the tubulin subunits lead to polymerisation and their loss, depolymerisation.[1] Stathmin regulates these by promoting depolymerization of microtubules or preventing polymerization of tubulin heterodimers.[2]
Stathmin interacts with two molecules of dimeric α,β-tubulin to form a tight ternary complex called the T2S complex.[3] One mole of stathmin binds to two moles of tubulin dimers through the stathmin-like domain (SLD).[5] When stathmin sequesters tubulin into the T2S complex, tubulin becomes non-polymerizable. Without tubulin polymerization, there is no microtubule assembly.[3] Stathmin also promotes microtubule disassembly by acting directly on the microtubule ends.[9]
The rate of microtubule assembly is an important aspect of cell growth therefore associating regulation of stathmin with cell cycle progress. Regulation of stathmin is cell cycle dependent and controlled by the cell’s protein kinases in response to specific cell signals.[5]Phosphorylation at four serine residues on stathmin named Ser16, Ser25, Ser38 and Ser63 causes weakened stathmin-tubulin binding. Stathmin phosphorylation increases the concentration of tubulin available in the cytoplasm for microtubule assembly. For cells to assemble the mitotic spindle necessary for initiation of the mitotic phase of the cell cycle, stathmin phosphorylation must occur. Without microtuble growth and assembly, the mitotic spindle cannot form, and the cell cycle is arrested. At cytokinesis, the last phase of the cell cycle, rapid dephosphorylation of stathmin occurs to block the cell from entering back into the cell cycle until it is ready.[5]
Clinical significance
Stathmin’s role in regulation of the cell cycle causes it to be an oncoprotein named oncoprotein 18 (op18). Stathmin (aka op18) can cause uncontrolled cell proliferation when mutated and not functioning properly. If stathmin is unable to bind to tubulin, it allows for constant microtubule assembly and therefore constant mitotic spindle assembly. With no regulation of the mitotic spindle, the cell cycle is capable of cycling uncontrollably resulting in the unregulated cell growth characteristic of cancer cells.[5]
Role in social behaviour
Mice without stathmin have deficiency in innate and learned fear. Stathmin−/− females do not assess threats well, leading to lack of innate parental care and adult social interactions. They lack motivation for retrieving pups and are unable to choose a safe location for nest-building. However, they have an enhancement in social interactions.[10]
↑ 2.02.1Rubin CI, Atweh GF (October 2004). "The role of stathmin in the regulation of the cell cycle". Journal of Cellular Biochemistry. 93 (2): 242–50. doi:10.1002/jcb.20187. PMID15368352.
↑ 3.03.13.23.3Jourdain L, Curmi P, Sobel A, Pantaloni D, Carlier MF (September 1997). "Stathmin: a tubulin-sequestering protein which forms a ternary T2S complex with two tubulin molecules". Biochemistry. 36 (36): 10817–21. doi:10.1021/bi971491b. PMID9312271.
↑Clément MJ, Jourdain I, Lachkar S, Savarin P, Gigant B, Knossow M, Toma F, Sobel A, Curmi PA (November 2005). "N-terminal stathmin-like peptides bind tubulin and impede microtubule assembly". Biochemistry. 44 (44): 14616–25. doi:10.1021/bi0512492. PMID16262261.
↑Maucuer A, Doye V, Sobel A (May 1990). "A single amino acid difference distinguishes the human and the rat sequences of stathmin, a ubiquitous intracellular phosphoprotein associated with cell regulations". FEBS Letters. 264 (2): 275–8. doi:10.1016/0014-5793(90)80266-L. PMID2358074.
↑Maucuer A, Moreau J, Méchali M, Sobel A (August 1993). "Stathmin gene family: phylogenetic conservation and developmental regulation in Xenopus". The Journal of Biological Chemistry. 268 (22): 16420–9. PMID8344928.
↑Doye V, Soubrier F, Bauw G, Boutterin MC, Beretta L, Koppel J, Vandekerckhove J, Sobel A (July 1989). "A single cDNA encodes two isoforms of stathmin, a developmentally regulated neuron-enriched phosphoprotein". The Journal of Biological Chemistry. 264 (21): 12134–7. PMID2745432.
↑Rubin CI, Atweh GF (October 2004). "The role of stathmin in the regulation of the cell cycle". Journal of Cellular Biochemistry. 93 (2): 242–50. doi:10.1002/jcb.20187. PMID15368352.
Sobel A (August 1991). "Stathmin: a relay phosphoprotein for multiple signal transduction?". Trends in Biochemical Sciences. 16 (8): 301–5. doi:10.1016/0968-0004(91)90123-D. PMID1957351.
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Melhem RF, Zhu XX, Hailat N, Strahler JR, Hanash SM (September 1991). "Characterization of the gene for a proliferation-related phosphoprotein (oncoprotein 18) expressed in high amounts in acute leukemia". The Journal of Biological Chemistry. 266 (27): 17747–53. PMID1917919.
Ferrari AC, Seuanez HN, Hanash SM, Atweh GF (July 1990). "A gene that encodes for a leukemia-associated phosphoprotein (p18) maps to chromosome bands 1p35-36.1". Genes, Chromosomes & Cancer. 2 (2): 125–9. doi:10.1002/gcc.2870020208. PMID2278968.
Maucuer A, Doye V, Sobel A (May 1990). "A single amino acid difference distinguishes the human and the rat sequences of stathmin, a ubiquitous intracellular phosphoprotein associated with cell regulations". FEBS Letters. 264 (2): 275–8. doi:10.1016/0014-5793(90)80266-L. PMID2358074.
Zhu XX, Kozarsky K, Strahler JR, Eckerskorn C, Lottspeich F, Melhem R, Lowe J, Fox DA, Hanash SM, Atweh GF (August 1989). "Molecular cloning of a novel human leukemia-associated gene. Evidence of conservation in animal species". The Journal of Biological Chemistry. 264 (24): 14556–60. PMID2760073.
Sobel A, Boutterin MC, Beretta L, Chneiweiss H, Doye V, Peyro-Saint-Paul H (March 1989). "Intracellular substrates for extracellular signaling. Characterization of a ubiquitous, neuron-enriched phosphoprotein (stathmin)". The Journal of Biological Chemistry. 264 (7): 3765–72. PMID2917975.
Kato S, Sekine S, Oh SW, Kim NS, Umezawa Y, Abe N, Yokoyama-Kobayashi M, Aoki T (December 1994). "Construction of a human full-length cDNA bank". Gene. 150 (2): 243–50. doi:10.1016/0378-1119(94)90433-2. PMID7821789.
Kumar R, Haugen JD (June 1994). "Human and rat osteoblast-like cells express stathmin, a growth-regulatory protein". Biochemical and Biophysical Research Communications. 201 (2): 861–5. doi:10.1006/bbrc.1994.1780. PMID8003023.
Brattsand G, Marklund U, Nylander K, Roos G, Gullberg M (March 1994). "Cell-cycle-regulated phosphorylation of oncoprotein 18 on Ser16, Ser25 and Ser38". European Journal of Biochemistry. 220 (2): 359–68. doi:10.1111/j.1432-1033.1994.tb18632.x. PMID8125092.
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Marklund U, Brattsand G, Shingler V, Gullberg M (July 1993). "Serine 25 of oncoprotein 18 is a major cytosolic target for the mitogen-activated protein kinase". The Journal of Biological Chemistry. 268 (20): 15039–47. PMID8325880.
Beretta L, Dobránsky T, Sobel A (September 1993). "Multiple phosphorylation of stathmin. Identification of four sites phosphorylated in intact cells and in vitro by cyclic AMP-dependent protein kinase and p34cdc2". The Journal of Biological Chemistry. 268 (27): 20076–84. PMID8376365.
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