galectin-9
{{cs1 config|name-list-style=vanc}}
{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
Galectin-9 was first isolated from mouse embryonic kidney in 1997 as a 36 kDa beta-galactoside lectin protein.{{cite journal | vauthors = Wada J, Kanwar YS | title = Identification and characterization of galectin-9, a novel beta-galactoside-binding mammalian lectin | journal = The Journal of Biological Chemistry | volume = 272 | issue = 9 | pages = 6078–86 | date = February 1997 | pmid = 9038233 | doi=10.1074/jbc.272.9.6078| doi-access = free }} Human galectin-9 is encoded by the LGALS9 gene.{{cite journal | vauthors = Türeci O, Schmitt H, Fadle N, Pfreundschuh M, Sahin U | title = Molecular definition of a novel human galectin which is immunogenic in patients with Hodgkin's disease | journal = The Journal of Biological Chemistry | volume = 272 | issue = 10 | pages = 6416–22 | date = March 1997 | pmid = 9045665 | doi = 10.1074/jbc.272.10.6416 | doi-access = free }}{{cite web | title = Entrez Gene: LGALS9 lectin, galactoside-binding, soluble, 9 (galectin 9)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3965}}
Function
The protein has N- and C- terminal carbohydrate-binding domains connected by a link peptide. Multiple alternatively spliced transcript variants have been found for this gene.
Galectin-9 is one of the most studied ligands for HAVCR2 (TIM-3) and is expressed on various tumor cells. However, it can also interact with other proteins (CLEC7A,{{cite journal | vauthors = Daley D, Mani VR, Mohan N, Akkad N, Ochi A, Heindel DW, Lee KB, Zambirinis CP, Pandian GS, Savadkar S, Torres-Hernandez A, Nayak S, Wang D, Hundeyin M, Diskin B, Aykut B, Werba G, Barilla RM, Rodriguez R, Chang S, Gardner L, Mahal LK, Ueberheide B, Miller G | display-authors = 6 | title = Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance | journal = Nature Medicine | volume = 23 | issue = 5 | pages = 556–567 | date = May 2017 | pmid = 28394331 | pmc = 5419876 | doi = 10.1038/nm.4314 }} CD137,{{cite journal | vauthors = Madireddi S, Eun SY, Lee SW, Nemčovičová I, Mehta AK, Zajonc DM, Nishi N, Niki T, Hirashima M, Croft M | title = Galectin-9 controls the therapeutic activity of 4-1BB-targeting antibodies | journal = The Journal of Experimental Medicine | volume = 211 | issue = 7 | pages = 1433–48 | date = June 2014 | pmid = 24958847 | pmc = 4076583 | doi = 10.1084/jem.20132687 }} CD40{{cite journal | vauthors = Vaitaitis GM, Wagner DH | title = Galectin-9 controls CD40 signaling through a Tim-3 independent mechanism and redirects the cytokine profile of pathogenic T cells in autoimmunity | journal = PLOS ONE | volume = 7 | issue = 6 | pages = e38708 | date = 2012 | pmid = 22685601 | pmc = 3369903 | doi = 10.1371/journal.pone.0038708 | bibcode = 2012PLoSO...738708V | doi-access = free }}). For example, an interaction with CD40 on T-cells inhibits their proliferation and induces cell death.
Galectin-9 also has important cytoplasmic, intracellular functions and controls AMPK{{cite journal | vauthors = Jia J, Abudu YP, Claude-Taupin A, Gu Y, Kumar S, Choi SW, Peters R, Mudd MH, Allers L, Salemi M, Phinney B, Johansen T, Deretic V | display-authors = 6 | title = Galectins Control mTOR in Response to Endomembrane Damage | journal = Molecular Cell | volume = 70 | issue = 1 | pages = 120–135.e8 | date = April 2018 | pmid = 29625033 | pmc = 5911935 | doi = 10.1016/j.molcel.2018.03.009 }}{{cite journal | vauthors = Jia J, Bissa B, Brecht L, Allers L, Choi SW, Gu Y, Zbinden M, Burge MR, Timmins G, Hallows K, Behrends C | display-authors = 6 |date= January 2020 |title=AMPK, a Regulator of Metabolism and Autophagy, Is Activated by Lysosomal Damage via a Novel Galectin-Directed Ubiquitin Signal Transduction System |journal=Molecular Cell | volume = 77 | issue = 5 |pages=951–969.e9|doi=10.1016/j.molcel.2019.12.028| pmid = 31995728 |pmc= 7785494 }} in response to lysosomal damage that can occur upon exposure to endogenous and exogenous membrane damaging agents such as crystalline silica, cholesterol crystals, microbial toxins, proteopathic aggregates such as tau fibrils and amyloids, and signaling pathways inducing lysosomal permeabilization such as those initiated by TRAIL.{{cite journal | vauthors = Werneburg NW, Guicciardi ME, Bronk SF, Kaufmann SH, Gores GJ | title = Tumor necrosis factor-related apoptosis-inducing ligand activates a lysosomal pathway of apoptosis that is regulated by Bcl-2 proteins | journal = The Journal of Biological Chemistry | volume = 282 | issue = 39 | pages = 28960–70 | date = September 2007 | pmid = 17686764 | doi = 10.1074/jbc.M705671200 | doi-access = free }} Mild lysosomal damage, such as that caused by the anti-diabetes drug metformin may contribute to the therapeutic action of metformin by activating AMPK. The mechanism of how Galectin-9 activates AMPK involves recognition of exposed lysosomal lumenal glycoproteins such as LAMP1, LAMP2, SCRAB2, TMEM192, etc., repulsion of deubiquitinating enzyme USP9X, increased K63 ubiquitination of TAK1 (MAP3K7) kinase, which in turn phopshorylates AMPK and activates it. This signaling cascade directly links Galectin-9 intracellular function with ubiquitin systems. Galectin-9, through its regulation of AMPK, a kinase that negatively regulates mTOR, cooperates with Galectin-8-based effects to inactivate mTOR downstream of the lysosomal damaging agents and conditions.
Clinical significance
The expression of galectin-9 has been detected on various hematological malignancies, such as CLL,{{cite journal | vauthors = Taghiloo S, Allahmoradi E, Ebadi R, Tehrani M, Hosseini-Khah Z, Janbabaei G, Shekarriz R, Asgarian-Omran H | title = Upregulation of Galectin-9 and PD-L1 Immune Checkpoints Molecules in Patients with Chronic Lymphocytic Leukemia | journal = Asian Pacific Journal of Cancer Prevention | volume = 18 | issue = 8 | pages = 2269–2274 | date = August 2017 | pmid = 28843266 | pmc = 5697491 | doi = 10.22034/APJCP.2017.18.8.2269 }} MDS,{{cite journal | vauthors = Asayama T, Tamura H, Ishibashi M, Kuribayashi-Hamada Y, Onodera-Kondo A, Okuyama N, Yamada A, Shimizu M, Moriya K, Takahashi H, Inokuchi K | title = Functional expression of Tim-3 on blasts and clinical impact of its ligand galectin-9 in myelodysplastic syndromes | journal = Oncotarget | volume = 8 | issue = 51 | pages = 88904–88917 | date = October 2017 | pmid = 29179486 | pmc = 5687656 | doi = 10.18632/oncotarget.21492 }} Hodgkin's lymphomas,{{cite journal |last1=Fujita |first1=Koji |last2=Iwama |first2=Hisakazu |last3=Oura |first3=Kyoko |last4=Tadokoro |first4=Tomoko |last5=Samukawa |first5=Eri |last6=Sakamoto |first6=Teppei |last7=Nomura |first7=Takako |last8=Tani |first8=Joji |last9=Yoneyama |first9=Hirohito |last10=Morishita |first10=Asahiro |last11=Himoto |first11=Takashi |last12=Hirashima |first12=Mitsuomi |last13=Masaki |first13=Tsutomu |title=Cancer Therapy Due to Apoptosis: Galectin-9 |journal=International Journal of Molecular Sciences |date=1 January 2017 |volume=18 |issue=1 |pages=74 |doi=10.3390/ijms18010074|doi-access=free |pmid=28045432 |pmc=5297709 }} AML{{cite journal | vauthors = Gonçalves Silva I, Yasinska IM, Sakhnevych SS, Fiedler W, Wellbrock J, Bardelli M, Varani L, Hussain R, Siligardi G, Ceccone G, Berger SM, Ushkaryov YA, Gibbs BF, Fasler-Kan E, Sumbayev VV | title = The Tim-3-galectin-9 Secretory Pathway is Involved in the Immune Escape of Human Acute Myeloid Leukemia Cells | journal = eBioMedicine | volume = 22 | pages = 44–57 | date = August 2017 | pmid = 28750861 | pmc = 5552242 | doi = 10.1016/j.ebiom.2017.07.018 }} or solid tumors, such as lung cancer,{{cite journal | vauthors = Gao J, Qiu X, Li X, Fan H, Zhang F, Lv T, Song Y | title = Expression profiles and clinical value of plasma exosomal Tim-3 and Galectin-9 in non-small cell lung cancer | journal = Biochemical and Biophysical Research Communications | volume = 498 | issue = 3 | pages = 409–415 | date = February 2018 | pmid = 29452091 | doi = 10.1016/j.bbrc.2018.02.114 }} breast cancer,{{cite journal | vauthors = Irie A, Yamauchi A, Kontani K, Kihara M, Liu D, Shirato Y, Seki M, Nishi N, Nakamura T, Yokomise H, Hirashima M | title = Galectin-9 as a prognostic factor with antimetastatic potential in breast cancer | journal = Clinical Cancer Research | volume = 11 | issue = 8 | pages = 2962–8 | date = April 2005 | pmid = 15837748 | doi = 10.1158/1078-0432.CCR-04-0861 | s2cid = 15041189 | doi-access = }} and hepatocellular carcinoma.{{cite journal | vauthors = Zhang ZY, Dong JH, Chen YW, Wang XQ, Li CH, Wang J, Wang GQ, Li HL, Wang XD | title = Galectin-9 acts as a prognostic factor with antimetastatic potential in hepatocellular carcinoma | journal = Asian Pacific Journal of Cancer Prevention | volume = 13 | issue = 6 | pages = 2503–9 | date = 2012 | pmid = 22938412 | doi=10.7314/apjcp.2012.13.6.2503| doi-access = free }}
HAVCR2/ galectin-9 interaction attenuated T-cell expansion and effectors function in tumor microenvironment and chronic infections.{{cite journal | vauthors = Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC | title = Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity | journal = The Journal of Experimental Medicine | volume = 207 | issue = 10 | pages = 2187–94 | date = September 2010 | pmid = 20819927 | pmc = 2947065 | doi = 10.1084/jem.20100643 | url = https://dash.harvard.edu/bitstream/handle/1/5265958/2947065.pdf?sequence=1 }} Moreover, galectin-9 contributed to tumorigenesis by tumor cell transformation, cell-cycle regulation, angiogenesis, and cell adhesion.{{cite journal |author-link1=Fu-Tong Liu | vauthors = Liu FT | title = Regulatory roles of galectins in the immune response | journal = International Archives of Allergy and Immunology | volume = 136 | issue = 4 | pages = 385–400 | date = April 2005 | pmid = 15775687 | doi = 10.1159/000084545 | s2cid = 6614531 }} The correlative studies analyzing the expression of galectin-9 and malignant clinical features showed controversial results. This can be explained as that galectin-9 can promote tumor immune escape as well as inhibit metastasis by promoting endothelial adhesion. Therefore many factors such as tumor type, stage, and the involvement of different galectins should be take into consideration when correlating the expression level and the malignancy.
Galectin-9, through its cytoplasmic action in control of AMPK, may affect various health conditions impacted by AMPK, including metabolism, obesity, diabetes, cancer, immune responses, and may be a part of the mechanism of action of the widely-prescribed anti-diabetes drug metformin.
References
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Further reading
{{refbegin | 2}}
- {{cite journal | vauthors = Hirashima M, Kashio Y, Nishi N, Yamauchi A, Imaizumi TA, Kageshita T, Saita N, Nakamura T | title = Galectin-9 in physiological and pathological conditions | journal = Glycoconjugate Journal | volume = 19 | issue = 7–9 | pages = 593–600 | year = 2004 | pmid = 14758084 | doi = 10.1023/B:GLYC.0000014090.63206.2f | s2cid = 11006101 }}
- {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1–2 | pages = 171–4 | date = January 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
- {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library | journal = Gene | volume = 200 | issue = 1–2 | pages = 149–56 | date = October 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }}
- {{cite journal | vauthors = Matsumoto R, Matsumoto H, Seki M, Hata M, Asano Y, Kanegasaki S, Stevens RL, Hirashima M | title = Human ecalectin, a variant of human galectin-9, is a novel eosinophil chemoattractant produced by T lymphocytes | journal = The Journal of Biological Chemistry | volume = 273 | issue = 27 | pages = 16976–84 | date = July 1998 | pmid = 9642261 | doi = 10.1074/jbc.273.27.16976 | doi-access = free }}
- {{cite journal | vauthors = Matsumoto R, Hirashima M, Kita H, Gleich GJ | title = Biological activities of ecalectin: a novel eosinophil-activating factor | journal = Journal of Immunology | volume = 168 | issue = 4 | pages = 1961–7 | date = February 2002 | pmid = 11823532 | doi = 10.4049/jimmunol.168.4.1961 | doi-access = free }}
- {{cite journal | vauthors = Kageshita T, Kashio Y, Yamauchi A, Seki M, Abedin MJ, Nishi N, Shoji H, Nakamura T, Ono T, Hirashima M | title = Possible role of galectin-9 in cell aggregation and apoptosis of human melanoma cell lines and its clinical significance | journal = International Journal of Cancer | volume = 99 | issue = 6 | pages = 809–16 | date = June 2002 | pmid = 12115481 | doi = 10.1002/ijc.10436 | s2cid = 205934076 | doi-access = free }}
- {{cite journal | vauthors = Imaizumi T, Kumagai M, Sasaki N, Kurotaki H, Mori F, Seki M, Nishi N, Fujimoto K, Tanji K, Shibata T, Tamo W, Matsumiya T, Yoshida H, Cui XF, Takanashi S, Hanada K, Okumura K, Yagihashi S, Wakabayashi K, Nakamura T, Hirashima M, Satoh K | title = Interferon-gamma stimulates the expression of galectin-9 in cultured human endothelial cells | journal = Journal of Leukocyte Biology | volume = 72 | issue = 3 | pages = 486–91 | date = September 2002 | doi = 10.1189/jlb.72.3.486 | pmid = 12223516 | s2cid = 17010289 }}
- {{cite journal | vauthors = Asakura H, Kashio Y, Nakamura K, Seki M, Dai S, Shirato Y, Abedin MJ, Yoshida N, Nishi N, Imaizumi T, Saita N, Toyama Y, Takashima H, Nakamura T, Ohkawa M, Hirashima M | title = Selective eosinophil adhesion to fibroblast via IFN-gamma-induced galectin-9 | journal = Journal of Immunology | volume = 169 | issue = 10 | pages = 5912–8 | date = November 2002 | pmid = 12421975 | doi = 10.4049/jimmunol.169.10.5912 | doi-access = free }}
- {{cite journal | vauthors = Kashio Y, Nakamura K, Abedin MJ, Seki M, Nishi N, Yoshida N, Nakamura T, Hirashima M | title = Galectin-9 induces apoptosis through the calcium-calpain-caspase-1 pathway | journal = Journal of Immunology | volume = 170 | issue = 7 | pages = 3631–6 | date = April 2003 | pmid = 12646627 | doi = 10.4049/jimmunol.170.7.3631 | doi-access = free }}
- {{cite journal | vauthors = Abedin MJ, Kashio Y, Seki M, Nakamura K, Hirashima M | title = Potential roles of galectins in myeloid differentiation into three different lineages | journal = Journal of Leukocyte Biology | volume = 73 | issue = 5 | pages = 650–6 | date = May 2003 | pmid = 12714580 | doi = 10.1189/jlb.0402163 | s2cid = 21337581 | doi-access = }}
- {{cite journal | vauthors = Matsuda A, Suzuki Y, Honda G, Muramatsu S, Matsuzaki O, Nagano Y, Doi T, Shimotohno K, Harada T, Nishida E, Hayashi H, Sugano S | title = Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways | journal = Oncogene | volume = 22 | issue = 21 | pages = 3307–18 | date = May 2003 | pmid = 12761501 | doi = 10.1038/sj.onc.1206406 | s2cid = 38880905 | doi-access = }}
- {{cite journal | vauthors = Irie A, Yamauchi A, Kontani K, Kihara M, Liu D, Shirato Y, Seki M, Nishi N, Nakamura T, Yokomise H, Hirashima M | title = Galectin-9 as a prognostic factor with antimetastatic potential in breast cancer | journal = Clinical Cancer Research | volume = 11 | issue = 8 | pages = 2962–8 | date = April 2005 | pmid = 15837748 | doi = 10.1158/1078-0432.CCR-04-0861 | s2cid = 15041189 | doi-access = }}
- {{cite journal | vauthors = Kasamatsu A, Uzawa K, Nakashima D, Koike H, Shiiba M, Bukawa H, Yokoe H, Tanzawa H | title = Galectin-9 as a regulator of cellular adhesion in human oral squamous cell carcinoma cell lines | journal = International Journal of Molecular Medicine | volume = 16 | issue = 2 | pages = 269–73 | date = August 2005 | pmid = 16012760 | doi = 10.3892/ijmm.16.2.269 }}
- {{cite journal | vauthors = Dai SY, Nakagawa R, Itoh A, Murakami H, Kashio Y, Abe H, Katoh S, Kontani K, Kihara M, Zhang SL, Hata T, Nakamura T, Yamauchi A, Hirashima M | title = Galectin-9 induces maturation of human monocyte-derived dendritic cells | journal = Journal of Immunology | volume = 175 | issue = 5 | pages = 2974–81 | date = September 2005 | pmid = 16116184 | doi = 10.4049/jimmunol.175.5.2974 | doi-access = free }}
- {{cite journal | vauthors = Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK | title = The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity | journal = Nature Immunology | volume = 6 | issue = 12 | pages = 1245–52 | date = December 2005 | pmid = 16286920 | doi = 10.1038/ni1271 | s2cid = 24886582 }}
- {{cite journal | vauthors = van de Weyer PS, Muehlfeit M, Klose C, Bonventre JV, Walz G, Kuehn EW | title = A highly conserved tyrosine of Tim-3 is phosphorylated upon stimulation by its ligand galectin-9 | journal = Biochemical and Biophysical Research Communications | volume = 351 | issue = 2 | pages = 571–6 | date = December 2006 | pmid = 17069754 | doi = 10.1016/j.bbrc.2006.10.079 }}
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External links
- {{PDBe-KB2|O00182|Galectin-9}}