Affinage

LGALS2

Galectin-2 · UniProt P05162

Round 2 corrected
Length
132 aa
Mass
14.6 kDa
Annotated
2026-04-28
42 papers in source corpus 4 papers cited in narrative 4 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Galectin-2 (LGALS2) is a β-galactoside-binding lectin that functions as an immunomodulatory and tumor-regulatory protein across multiple tissue contexts. It directly binds lymphotoxin-alpha (LTA) in vascular smooth muscle cells and macrophages within atherosclerotic lesions, linking it to inflammatory signaling in myocardial infarction pathogenesis (PMID:15129282). In colon cancer, galectin-2 suppresses tumor growth by inhibiting STAT3 phosphorylation, as demonstrated by enlarged tumors with elevated phospho-STAT3 in Lgals2-knockout mice (PMID:33110234), while in triple-negative breast cancer it drives an immunosuppressive microenvironment by promoting M2-like macrophage polarization and proliferation through the CSF1/CSF1R axis, and antibody-mediated blockade of LGALS2 reverses this immune evasion and arrests tumor growth (PMID:35767614).

Mechanistic history

Synthesis pass · year-by-year structured walk · 3 steps
  1. 2004 High

    The first mechanistic link for galectin-2 was established by showing it directly binds lymphotoxin-alpha and that a cis-regulatory SNP modulates LGALS2 transcription, thereby altering LTA secretion and connecting galectin-2 to inflammatory vascular disease.

    Evidence Protein–protein binding assay, in vitro transcriptional reporter assay for SNP effect, and immunohistochemistry co-localization in human atherosclerotic lesions

    PMID:15129282

    Open questions at the time
    • Structural basis of the galectin-2–LTA interaction is undefined
    • Whether galectin-2/LTA binding is carbohydrate-dependent or protein–protein mediated is not resolved
    • Causal role in atherosclerosis progression not tested by genetic intervention in vivo
  2. 2020 High

    A direct tumor-suppressive mechanism was identified: galectin-2 inhibits STAT3 phosphorylation in colonic epithelial cells, and Lgals2-knockout mice develop significantly larger colon tumors with hyperactivated STAT3, establishing galectin-2 as a negative regulator of STAT3 signaling in colorectal tumorigenesis.

    Evidence Genome-wide CRISPR screen, Lgals2-knockout mouse model with AOM/DSS-induced tumors, and overexpression/knockdown in human colon cancer cells with phospho-STAT3 readout

    PMID:33110234

    Open questions at the time
    • Whether galectin-2 directly binds STAT3 or acts via an upstream mediator is unknown
    • The opposing effect of Gal2 deficiency in colitis versus tumorigenesis is mechanistically unresolved
    • Relevance of the LTA-binding function to the colon tumor context not examined
  3. 2022 High

    Two studies expanded the cancer biology of galectin-2 in opposite directions: in triple-negative breast cancer, tumor-derived LGALS2 promotes immunosuppression by driving M2-like macrophage polarization via CSF1/CSF1R signaling, while in papillary thyroid carcinoma, LGALS2 suppresses proliferation and induces apoptosis through PI3K/AKT pathway activation.

    Evidence In vivo CRISPR screens in multiple mouse TNBC models with antibody blockade and transcriptomic validation [PMID:35767614]; overexpression/knockdown in PTC cell lines with xenograft confirmation and PI3K/AKT immunoblotting [PMID:36221286]

    PMID:35767614 PMID:36221286

    Open questions at the time
    • The direct receptor or binding partner mediating CSF1/CSF1R axis activation by galectin-2 is unidentified
    • PI3K/AKT activation mechanism by galectin-2 in thyroid cancer is characterized only at the pathway level without a defined molecular target
    • How galectin-2 exerts pro-tumorigenic effects in breast cancer but anti-tumorigenic effects in colon and thyroid cancer is not reconciled

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular basis for galectin-2's context-dependent tumor-promoting versus tumor-suppressive activities remains unresolved, and no unifying model connects its lectin-binding properties to the distinct downstream pathways (STAT3, PI3K/AKT, CSF1/CSF1R) engaged in different tissues.
  • No structural data for galectin-2 in complex with any signaling partner
  • Whether carbohydrate recognition is required for each downstream signaling outcome has not been tested
  • No integrative study has compared galectin-2 interactomes across tissue types

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4
Localization
GO:0005576 extracellular region 2
Pathway
R-HSA-1643685 Disease 3 R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2
Partners
CSF1RLTASTAT3

Evidence

Reading pass · 4 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 Galectin-2 (LGALS2) directly binds lymphotoxin-alpha (LTA) protein, and a functional SNP in LGALS2 affects its transcriptional level in vitro, leading to altered LTA secretion. Both galectin-2 and LTA are co-expressed in smooth muscle cells and macrophages in human atherosclerotic lesions, placing galectin-2 in the LTA inflammatory cascade relevant to myocardial infarction pathogenesis. Protein-protein binding assay (galectin-2/LTA interaction), in vitro transcriptional reporter assay for SNP effect on LGALS2 expression, immunohistochemistry for co-localization in atherosclerotic tissue Nature High 15129282
2022 Tumor cell-intrinsic Lgals2 promotes an immunosuppressive microenvironment in triple-negative breast cancer by inducing increased numbers of tumor-associated macrophages and driving their M2-like polarization and proliferation through the CSF1/CSF1R signaling axis. Blockade of LGALS2 with an inhibitory antibody arrested tumor growth and reversed immune suppression. In vivo CRISPR screens in multiple mouse TNBC models, transcriptomic analysis, functional antibody blockade, macrophage polarization assays Science advances High 35767614
2020 Galectin-2 (Gal2/LGALS2) suppresses colon tumor growth by inhibiting STAT3 phosphorylation. Gal2 overexpression in human colon tumor epithelial cells decreased proliferation and blunted H2O2-induced STAT3 phosphorylation, while Gal2-KO mice developed significantly larger tumors with markedly increased STAT3 phosphorylation compared to wild-type. Additionally, Gal2 deficiency ameliorated DSS-induced acute colitis, indicating a role in regulating oxidative stress responses in the colon. Genome-wide CRISPR knockout screen (NGS), Lgals2 knockout mouse model (DSS colitis and AOM/DSS tumorigenesis), LGALS2 overexpression and knockdown in human colon cancer cells, Western blot for STAT3 phosphorylation, CCK-8 proliferation assay Oncogene High 33110234
2022 LGALS2 suppresses papillary thyroid carcinoma (PTC) cell proliferation and promotes apoptosis via activation of the PI3K/AKT pathway. LGALS2 knockdown enhanced PTC cell proliferative activity and reduced apoptotic sensitivity, while LGALS2 overexpression had the opposite effect both in vitro and in a murine xenograft model. LGALS2 overexpression (pcDNA4.0 vector) and siRNA knockdown in PTC cell lines, CCK-8 assay, EdU uptake assay, apoptosis assay, murine xenograft model, Western immunoblotting for PI3K/AKT pathway components Gland surgery Medium 36221286

Source papers

Stage 0 corpus · 42 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1994 Galectins. Structure and function of a large family of animal lectins. The Journal of biological chemistry 1222 8063692
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
1996 Expression of galectin-3 modulates T-cell growth and apoptosis. Proceedings of the National Academy of Sciences of the United States of America 661 8692888
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Large-scale proteomics and phosphoproteomics of urinary exosomes. Journal of the American Society of Nephrology : JASN 607 19056867
2009 The B7 family member B7-H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans. The Journal of experimental medicine 547 19528259
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
2006 Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. Cell 517 17110338
2006 Galectin-3 regulates myofibroblast activation and hepatic fibrosis. Proceedings of the National Academy of Sciences of the United States of America 513 16549783
2010 Predictive value of plasma galectin-3 levels in heart failure with reduced and preserved ejection fraction. Annals of medicine 465 21189092
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2000 Human galectin-3 is a novel chemoattractant for monocytes and macrophages. Journal of immunology (Baltimore, Md. : 1950) 409 10925302
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2016 TRIMs and Galectins Globally Cooperate and TRIM16 and Galectin-3 Co-direct Autophagy in Endomembrane Damage Homeostasis. Developmental cell 386 27693506
2010 Prognostic value of galectin-3, a novel marker of fibrosis, in patients with chronic heart failure: data from the DEAL-HF study. Clinical research in cardiology : official journal of the German Cardiac Society 378 20130888
1998 X-ray crystal structure of the human galectin-3 carbohydrate recognition domain at 2.1-A resolution. The Journal of biological chemistry 356 9582341
1995 Expression and function of galectin-3, a beta-galactoside-binding lectin, in human monocytes and macrophages. The American journal of pathology 340 7573347
2017 Galectin-3 as a novel biomarker for disease diagnosis and a target for therapy (Review). International journal of molecular medicine 335 29207027
2013 Endogenous purification reveals GREB1 as a key estrogen receptor regulatory factor. Cell reports 307 23403292
2012 Galectin-3 mediates aldosterone-induced vascular fibrosis. Arteriosclerosis, thrombosis, and vascular biology 286 23117656
2004 NG2 proteoglycan promotes endothelial cell motility and angiogenesis via engagement of galectin-3 and alpha3beta1 integrin. Molecular biology of the cell 281 15181153
2004 Functional variation in LGALS2 confers risk of myocardial infarction and regulates lymphotoxin-alpha secretion in vitro. Nature 199 15129282
2022 In vivo multidimensional CRISPR screens identify Lgals2 as an immunotherapy target in triple-negative breast cancer. Science advances 61 35767614
2020 Genome-wide CRISPR screen identifies LGALS2 as an oxidative stress-responsive gene with an inhibitory function on colon tumor growth. Oncogene 29 33110234
2024 Deciphering the role of LGALS2: insights into tertiary lymphoid structure-associated dendritic cell activation and immunotherapeutic potential in breast cancer patients. Molecular cancer 25 39350165
2015 PPARG, AGTR1, CXCL16 and LGALS2 polymorphisms are correlated with the risk for coronary heart disease. International journal of clinical and experimental pathology 21 26045830
2006 LGALS2 functional variant rs7291467 is not associated with susceptibility to myocardial infarction in Caucasians. Atherosclerosis 17 17098239
1993 Two members of the S-lac lectin gene family, LGALS1 and LGALS2, reside in close proximity on human chromosome 22q12-q13. Genomics 17 8449510
2016 Genetic association between inflammatory genes (IL-1α, CD14, LGALS2, PSMA6) and risk of ischemic stroke: A meta-analysis. Meta gene 15 27014587
2021 Gene polymorphisms of LGALS2, LGALS3 and LGALS9 in patients with rheumatoid arthritis. Cellular immunology 9 34371260
2006 Genotype of galectin 2 (LGALS2) is associated with insulin-glucose profile in the British Women's Heart and Health Study. Diabetologia 9 16468038
2023 Investigation of LGALS2 expression in the TCGA database reveals its clinical relevance in breast cancer immunotherapy and drug resistance. Scientific reports 5 37838802
2022 LGALS2 suppresses the progression of papillary thyroid carcinoma by regulating the PI3K/AKT pathway. Gland surgery 3 36221286