Stathmin

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

STMN1
Identifiers
AliasesSTMN1, C1orf215, LAP18, Lag, OP18, PP17, PP19, PR22, SMN, stathmin 1
External IDsOMIM: 151442 MGI: 96739 HomoloGene: 4063 GeneCards: STMN1
Gene location (Human)
Chr.Chromosome 1 (human)[1]
Band1p36.11Start25,884,181 bp[1]
End25,906,991 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

3925

16765

Ensembl

ENSG00000117632

ENSMUSG00000028832

UniProt

P16949

P54227

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

Location (UCSC)Chr 1: 25.88 – 25.91 MbChr 4: 134.47 – 134.47 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5] More specifically, stathmin is crucial in regulating the cell cycle.[6] It is found solely in eukaryotes.

Its function as an important regulatory protein of microtubule dynamics has been well-characterized.[7] 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.[8]

At low concentrations of free tubulin, the growth rate at the microtubule ends is slowed and results in an increased rate of depolymerization (disassembly).[7][9]

Structure

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

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.[5] Stathmin regulates these by promoting depolymerization of microtubules or preventing polymerization of tubulin heterodimers.[6]

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,[10] functioning through a variety of second messengers.

Its phosphorylation and gene expression are regulated throughout development [11] and in response to extracellular signals regulating cell proliferation, differentiation and function.[12]

Interactions
Stathmin
Structure of Tubulin-Colchicine-Vinblastine: Stathmin-like domain complex
Identifiers
SymbolStathmin
PfamPF00836
InterProIPR000956
PROSITEPDOC00487
SCOPe1sa0 / SUPFAM

Stathmin interacts with two molecules of dimeric α,β-tubulin to form a tight ternary complex called the T2S complex.[7] One mole of stathmin binds to two moles of tubulin dimers through the stathmin-like domain (SLD).[9] When stathmin sequesters tubulin into the T2S complex, tubulin becomes non-polymerizable. Without tubulin polymerization, there is no microtubule assembly.[7] Stathmin also promotes microtubule disassembly by acting directly on the microtubule ends.[6]

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.[9] 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.[9]

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.[9]

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.[13]

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References
  1. GRCh38: Ensembl release 89: ENSG00000117632 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000028832 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Kueh HY, Mitchison TJ (August 2009). "Structural plasticity in actin and tubulin polymer dynamics". Science. 325 (5943): 960–3. Bibcode:2009Sci...325..960K. doi:10.1126/science.1168823. PMC 2864651. PMID 19696342.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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. Bibcode:2008PNAS..10514620M. doi:10.1073/pnas.0807507105. PMC 2567152. PMID 18794533.

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