Stathmin

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STMN1
Identifiers
Aliases STMN1, C1orf215, LAP18, Lag, OP18, PP17, PP19, PR22, SMN, stathmin 1
External IDs OMIM: 151442 MGI: 96739 HomoloGene: 4063 GeneCards: STMN1
RNA expression pattern
PBB GE STMN1 200783 s at fs.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_203401
NM_001145454
NM_005563
NM_152497
NM_203399

NM_019641

RefSeq (protein)

NP_001138926
NP_005554
NP_981944
NP_981946

NP_062615.1
NP_062615

Location (UCSC) Chr 1: 25.88 – 25.91 Mb Chr 4: 134.47 – 134.47 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

Stathmin, also known as metablastin and oncoprotein 18 is a protein that in humans is encoded by the STMN1 gene.

Stathmin is a highly conserved 17 kDa protein 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.[3] More specifically, stathmin is crucial in regulating the cell cycle.[4] It is found solely in eukaryotes.

Its function as an important regulatory protein of microtubule dynamics has been well-characterized.[5] 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.[6]

At low concentrations of free tubulin, the growth rate at the microtubule ends is slowed and results in an increased rate of depolymerization (disassembly).[5][7]

Structure[edit]

Stathmin, and the related proteins SCG10 and XB3, contain a N-terminal domain (XB3 contains an additional N-terminal hydrophobic region), a 78 amino acid coiled-coil region, and a short C-terminal domain.

Function[edit]

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 tubulin heterodimers. The changes in cytoskeleton are known as microtubule dynamics; the addition of the tubulin subunits lead to polymerisation and their loss, depolymerisation.[3] Stathmin regulates these by promoting depolymerization of microtubules or preventing polymerization of tubulin heterodimers.[4]

Additionally, Stathmin is thought to have a role in cell signaling pathway. Stathmin is a ubiquitous phosphorylated protein which makes it act as an intracellular relay for diverse regulatory pathways,[8] functioning through a variety of second messengers.

Its phosphorylation and gene expression are regulated throughout development [9] and in response to extracellular signals regulating cell proliferation, differentiation and function.[10]

Interactions[edit]

Stathmin
PDB 1z2b EBI.jpg
Structure of Tubulin-Colchicine-Vinblastine: Stathmin-like domain complex
Identifiers
Symbol Stathmin
Pfam PF00836
InterPro IPR000956
PROSITE PDOC00487
SCOP 1sa0
SUPERFAMILY 1sa0

Stathmin interacts with two molecules of dimeric α,β-tubulin to form a tight ternary complex called the T2S complex.[5] One mole of stathmin binds to two moles of tubulin dimers through the stathmin-like domain (SLD).[7] When stathmin sequesters tubulin into the T2S complex, tubulin becomes non-polymerizable. Without tubulin polymerization, there is no microtubule assembly.[5] Stathmin also promotes microtubule disassembly by acting directly on the microtubule ends.[11]

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.[7] 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.[7]

Clinical significance[edit]

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.[7]

Role in social behaviour[edit]

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.[12]

References[edit]

  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ a b Kueh HY, Mitchison TJ (August 2009). "Structural plasticity in actin and tubulin polymer dynamics". Science. 325 (5943): 960–3. doi:10.1126/science.1168823. PMC 2864651Freely accessible. PMID 19696342. 
  4. ^ a b 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. PMID 15368352. 
  5. ^ a b c d Jourdain 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. PMID 9312271. 
  6. ^ 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. PMID 16262261. 
  7. ^ a b c d e Cassimeris L (February 2002). "The oncoprotein 18/stathmin family of microtubule destabilizers". Current Opinion in Cell Biology. 14 (1): 18–24. doi:10.1016/S0955-0674(01)00289-7. PMID 11792540. 
  8. ^ 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. PMID 2358074. 
  9. ^ 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. PMID 8344928. 
  10. ^ 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. PMID 2745432. 
  11. ^ 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. PMID 15368352. 
  12. ^ Martel G, Nishi A, Shumyatsky GP (September 2008). "Stathmin reveals dissociable roles of the basolateral amygdala in parental and social behaviors". Proceedings of the National Academy of Sciences of the United States of America. 105 (38): 14620–5. doi:10.1073/pnas.0807507105. PMC 2567152Freely accessible. PMID 18794533. 

Further reading[edit]

  • 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. PMID 1957351. 
  • Steinmetz MO (May 2007). "Structure and thermodynamics of the tubulin-stathmin interaction". Journal of Structural Biology. 158 (2): 137–47. doi:10.1016/j.jsb.2006.07.018. PMID 17029844. 
  • Doye V, Le Gouvello S, Dobransky T, Chneiweiss H, Beretta L, Sobel A (October 1992). "Expression of transfected stathmin cDNA reveals novel phosphorylated forms associated with developmental and functional cell regulation". The Biochemical Journal. 287 ( Pt 2) (Pt 2): 549–54. PMC 1133199Freely accessible. PMID 1445213. 
  • Labdon JE, Nieves E, Schubart UK (February 1992). "Analysis of phosphoprotein p19 by liquid chromatography/mass spectrometry. Identification of two proline-directed serine phosphorylation sites and a blocked amino terminus". The Journal of Biological Chemistry. 267 (5): 3506–13. PMID 1737801. 
  • 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. PMID 1917919. 
  • 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. PMID 2278968. 
  • 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. PMID 2358074. 
  • 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. PMID 2760073. 
  • 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. PMID 2917975. 
  • Maucuer A, Camonis JH, Sobel A (April 1995). "Stathmin interaction with a putative kinase and coiled-coil-forming protein domains". Proceedings of the National Academy of Sciences of the United States of America. 92 (8): 3100–4. doi:10.1073/pnas.92.8.3100. PMC 42112Freely accessible. PMID 7724523. 
  • 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. PMID 7821789. 
  • Curmi PA, Maucuer A, Asselin S, Lecourtois M, Chaffotte A, Schmitter JM, Sobel A (June 1994). "Molecular characterization of human stathmin expressed in Escherichia coli: site-directed mutagenesis of two phosphorylatable serines (Ser-25 and Ser-63)". The Biochemical Journal. 300 ( Pt 2) (Pt 2): 331–8. PMC 1138166Freely accessible. PMID 8002936. 
  • 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. PMID 8003023. 
  • 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. PMID 8125092. 
  • Marklund U, Brattsand G, Osterman O, Ohlsson PI, Gullberg M (December 1993). "Multiple signal transduction pathways induce phosphorylation of serines 16, 25, and 38 of oncoprotein 18 in T lymphocytes". The Journal of Biological Chemistry. 268 (34): 25671–80. PMID 8245003. 
  • 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. PMID 8325880. 
  • 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. PMID 8376365. 
  • Hosoya H, Ishikawa K, Dohi N, Marunouchi T (August 1996). "Transcriptional and post-transcriptional regulation of pr22 (Op18) with proliferation control". Cell Structure and Function. 21 (4): 237–43. doi:10.1247/csf.21.237. PMID 8906359. 
  • Larsson N, Marklund U, Gradin HM, Brattsand G, Gullberg M (September 1997). "Control of microtubule dynamics by oncoprotein 18: dissection of the regulatory role of multisite phosphorylation during mitosis". Molecular and Cellular Biology. 17 (9): 5530–9. PMC 232401Freely accessible. PMID 9271428. 

External links[edit]

This article incorporates text from the public domain Pfam and InterPro IPR000956