# STMN1

## Overview
STMN1 is a gene that encodes the protein stathmin 1, a cytosolic phosphoprotein involved in the regulation of microtubule dynamics. Stathmin 1 is categorized as a microtubule regulatory protein, playing a pivotal role in cellular processes such as cell division, motility, and adhesion by modulating the stability of microtubules through the sequestration of tubulin. The protein is ubiquitously expressed across various cell types, including neurons, where it is integral to synaptic stability and memory consolidation. The activity of stathmin 1 is finely regulated by phosphorylation, which affects its interaction with tubulin and its function in neuronal morphogenesis. Dysregulation of STMN1 expression is associated with several cancers and neurological disorders, making it a potential biomarker and therapeutic target (Ringhoff2009Gene; Gagliardi2022Stathmins; Chauvin2015Neuronal).

## Structure
Stathmin 1 (STMN1) is a cytosolic phosphoprotein composed of 149 amino acids, with a molecular weight of approximately 19 kDa (Rana2008Stathmin). The protein is organized into four domains, with the core region being essential for tubulin interaction. This core requires either an N- or C-terminal extension for full functionality (Rana2008Stathmin). The N-terminal region of STMN1 caps α-tubulin subunits, preventing further protofilament longitudinal contacts, while the core binds along the length of the α/β heterodimers (Rana2008Stathmin).

STMN1 features a conserved coiled-coil stathmin-like domain (SLD) at the C-terminal, which is crucial for binding and releasing tubulin after phosphorylation (Gagliardi2022Stathmins). The secondary structure includes an α-helical domain associated with amino acids 44-138, which binds to tubulin subunits (Rana2008Stathmin). 

Post-translational modifications of STMN1 include phosphorylation at specific serine residues, notably Ser 16, 25, 38, and 63. Phosphorylation at these sites regulates its interaction with tubulin and its role in microtubule dynamics (Gagliardi2022Stathmins; Rana2008Stathmin). The phosphorylation of Ser63, in particular, leads to a change in the protein's secondary structure, reducing its binding to α/β-tubulin heterodimers (Gagliardi2022Stathmins).

## Function
Stathmin 1 (STMN1) is a microtubule regulatory protein that plays a crucial role in maintaining microtubule dynamics within cells. It functions primarily by destabilizing microtubules through the sequestration of free tubulin, which is essential for processes such as cell division, motility, and adhesion (Ringhoff2009Gene; Chauvin2015Neuronal). In healthy human cells, STMN1 is involved in the regulation of the microtubule cytoskeleton, impacting cell motility and adhesion by influencing the expression of a cohort of proteins rather than directly altering microtubule assembly (Ringhoff2009Gene).

STMN1 is ubiquitously expressed in various cell types, including neurons, where it integrates diverse regulatory pathways in response to extracellular signals (Chauvin2015Neuronal). It is particularly important in the nervous system, where it regulates synaptic stability and memory consolidation by affecting microtubule stability and the dendritic transport of the GluA2 subunit of AMPA-type glutamate receptors (Chauvin2015Neuronal). The protein's activity is modulated by phosphorylation, which influences its interaction with tubulin and its regulatory functions in neuronal morphogenesis (Chauvin2015Neuronal). Despite its critical roles, STMN1 knockout studies in mice suggest compensatory mechanisms among stathmin family proteins, as these mice develop normally with only mild phenotypic changes (Chauvin2015Neuronal).

## Clinical Significance
Alterations in the expression of the STMN1 gene are associated with various cancers and neurological disorders. In breast cancer, high STMN1 expression is linked to aggressive subtypes, such as triple-negative breast cancers, and is associated with poor prognosis and treatment resistance (Obayashi2017Stathmin1). In colorectal cancer, STMN1 overexpression correlates with increased metastatic potential and poor survival outcomes, making it a potential therapeutic target (Tan2012Proteomic; Tan2018Label‐Free). Similarly, in hepatocellular carcinoma, STMN1 overexpression is associated with early recurrence and poor prognosis, and its silencing reduces tumor invasiveness (Hsieh2010Stathmin1).

STMN1 is also implicated in non-small cell lung cancer, where its overexpression is linked to poor tumor differentiation and shorter disease-specific survival (Nie2015Overexpression). In neurological disorders, STMN1 is involved in motor neuron diseases such as spinal muscular atrophy, where its upregulation correlates with disease severity (Gagliardi2022Stathmins). These findings suggest that STMN1 plays a significant role in cancer progression and neurological disease pathogenesis, highlighting its potential as a biomarker and therapeutic target.

## Interactions
Stathmin 1 (STMN1) is a phosphoprotein that plays a crucial role in regulating microtubule dynamics by interacting with various proteins. It directly binds to the human PIWIL1 protein, which up-regulates STMN1 expression by inhibiting its ubiquitin-mediated degradation. This interaction is dependent on the E3 ubiquitin ligase RLIM and occurs mainly in the cytoplasm, involving the PIWI domain of PIWIL1 and the N-terminal region of STMN1 (Li2015PIWIL1).

STMN1 also interacts with the chromokinesin KIF4A in a SUMO-dependent manner. SUMOylation of KIF4A enhances its binding to STMN1, which is essential for regulating abscission during cell division. This interaction facilitates timely separation of daughter cells by promoting local microtubule destabilization (Cuijpers2020Chromokinesin).

In the context of liver cancer, STMN1 interacts with YAP1, a key player in the Hippo signaling pathway. STMN1 upregulation activates YAP1 signaling, promoting its nuclear localization and interaction with transcription factors, which enhances liver cancer cell proliferation and tumorigenesis (liu2020stathmin).

STMN1 is also involved in a ternary complex with AICD, FE65, and TIP60, which down-regulates its expression. This complex formation is part of the regulatory mechanisms involving STMN1 in cellular processes (Müller2013A).


## References


[1. (Gagliardi2022Stathmins) Delia Gagliardi, Elisa Pagliari, Megi Meneri, Valentina Melzi, Federica Rizzo, Giacomo Pietro Comi, Stefania Corti, Michela Taiana, and Monica Nizzardo. Stathmins and motor neuron diseases: pathophysiology and therapeutic targets. Biomedicines, 10(3):711, March 2022. URL: http://dx.doi.org/10.3390/biomedicines10030711, doi:10.3390/biomedicines10030711. This article has 11 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/biomedicines10030711)

[2. (Hsieh2010Stathmin1) Sen‐Yung Hsieh, Shiu‐Feng Huang, Ming‐Chin Yu, Ta‐Sen Yeh, Tse‐Chin Chen, Yu‐Jr Lin, Chee‐Jen Chang, Chang‐Mung Sung, Yun‐Lin Lee, and Chih‐Yun Hsu. Stathmin1 overexpression associated with polyploidy, tumor‐cell invasion, early recurrence, and poor prognosis in human hepatoma. Molecular Carcinogenesis, 49(5):476–487, March 2010. URL: http://dx.doi.org/10.1002/mc.20627, doi:10.1002/mc.20627. This article has 91 citations and is from a peer-reviewed journal.](https://doi.org/10.1002/mc.20627)

[3. (Obayashi2017Stathmin1) Sayaka Obayashi, Jun Horiguchi, Toru Higuchi, Ayaka Katayama, Tadashi Handa, Bolag Altan, Tuya Bai, Pinjie Bao, Halin Bao, Takehiko Yokobori, Masahiko Nishiyama, Tetsunari Oyama, and Hiroyuki Kuwano. Stathmin1 expression is associated with aggressive phenotypes and cancer stem cell marker expression in breast cancer patients. International Journal of Oncology, 51(3):781–790, July 2017. URL: http://dx.doi.org/10.3892/ijo.2017.4085, doi:10.3892/ijo.2017.4085. This article has 36 citations and is from a peer-reviewed journal.](https://doi.org/10.3892/ijo.2017.4085)

[4. (Tan2012Proteomic) Hwee Tong Tan, Wei Wu, Yi Zhen Ng, Xuxiao Zhang, Benedict Yan, Chee Wee Ong, Sandra Tan, Manuel Salto-Tellez, Shing Chuan Hooi, and Maxey C. M. Chung. Proteomic analysis of colorectal cancer metastasis: stathmin-1 revealed as a player in cancer cell migration and prognostic marker. Journal of Proteome Research, 11(2):1433–1445, January 2012. URL: http://dx.doi.org/10.1021/pr2010956, doi:10.1021/pr2010956. This article has 46 citations and is from a peer-reviewed journal.](https://doi.org/10.1021/pr2010956)

[5. (Nie2015Overexpression) Wei Nie, Mi-die Xu, Lu Gan, Hai Huang, Qingyu Xiu, and Bing Li. Overexpression of stathmin 1 is a poor prognostic biomarker in non-small cell lung cancer. Laboratory Investigation, 95(1):56–64, January 2015. URL: http://dx.doi.org/10.1038/labinvest.2014.124, doi:10.1038/labinvest.2014.124. This article has 57 citations and is from a peer-reviewed journal.](https://doi.org/10.1038/labinvest.2014.124)

[6. (Cuijpers2020Chromokinesin) Sabine A. G. Cuijpers, Edwin Willemstein, Jan G. Ruppert, Daphne M. van Elsland, William C. Earnshaw, and Alfred C. O. Vertegaal. Chromokinesin kif4a teams up with stathmin 1 to regulate abscission in a sumo-dependent manner. Journal of Cell Science, July 2020. URL: http://dx.doi.org/10.1242/jcs.248591, doi:10.1242/jcs.248591. This article has 7 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1242/jcs.248591)

7. (liu2020stathmin) Y-P Liu, L-L Pan, and C-C Kong. Stathmin 1 promotes the progression of liver cancer through interacting with yap1. European Review for Medical & Pharmacological Sciences, 2020. This article has 18 citations.

[8. (Chauvin2015Neuronal) Stéphanie Chauvin and André Sobel. Neuronal stathmins: a family of phosphoproteins cooperating for neuronal development, plasticity and regeneration. Progress in Neurobiology, 126:1–18, March 2015. URL: http://dx.doi.org/10.1016/j.pneurobio.2014.09.002, doi:10.1016/j.pneurobio.2014.09.002. This article has 84 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.pneurobio.2014.09.002)

[9. (Müller2013A) Thorsten Müller, Andreas Schrötter, Christina Loosse, Kathy Pfeiffer, Carsten Theiss, Marion Kauth, Helmut E. Meyer, and Katrin Marcus. A ternary complex consisting of aicd, fe65, and tip60 down-regulates stathmin1. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 1834(1):387–394, January 2013. URL: http://dx.doi.org/10.1016/j.bbapap.2012.07.017, doi:10.1016/j.bbapap.2012.07.017. This article has 32 citations.](https://doi.org/10.1016/j.bbapap.2012.07.017)

[10. (Li2015PIWIL1) Chao Li, Xiaoyan Zhou, Jianhui Chen, Yilu Lu, Qianqian Sun, Dachang Tao, Wei Hu, Xulei Zheng, Shasha Bian, Yunqiang Liu, and Yongxin Ma. Piwil1 destabilizes microtubule by suppressing phosphorylation at ser16 and rlim-mediated degradation of stathmin1. Oncotarget, 6(29):27794–27804, July 2015. URL: http://dx.doi.org/10.18632/oncotarget.4533, doi:10.18632/oncotarget.4533. This article has 18 citations and is from a poor quality or predatory journal.](https://doi.org/10.18632/oncotarget.4533)

[11. (Ringhoff2009Gene) Danielle N Ringhoff and Lynne Cassimeris. Gene expression profiles in mouse embryo fibroblasts lacking stathmin, a microtubule regulatory protein, reveal changes in the expression of genes contributing to cell motility. BMC Genomics, 10(1):343, 2009. URL: http://dx.doi.org/10.1186/1471-2164-10-343, doi:10.1186/1471-2164-10-343. This article has 14 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/1471-2164-10-343)

[12. (Tan2018Label‐Free) Hwee Tong Tan and Maxey Ching Ming Chung. Label‐free quantitative phosphoproteomics reveals regulation of vasodilator‐stimulated phosphoprotein upon stathmin‐1 silencing in a pair of isogenic colorectal cancer cell lines. PROTEOMICS, March 2018. URL: http://dx.doi.org/10.1002/pmic.201700242, doi:10.1002/pmic.201700242. This article has 11 citations and is from a peer-reviewed journal.](https://doi.org/10.1002/pmic.201700242)

[13. (Rana2008Stathmin) Shushan Rana, Phillip B Maples, Neil Senzer, and John Nemunaitis. Stathmin 1: a novel therapeutic target for anticancer activity. Expert Review of Anticancer Therapy, 8(9):1461–1470, September 2008. URL: http://dx.doi.org/10.1586/14737140.8.9.1461, doi:10.1586/14737140.8.9.1461. This article has 211 citations and is from a peer-reviewed journal.](https://doi.org/10.1586/14737140.8.9.1461)