Galectin-3 (Gal-3) regulates basic cellular functions such as cell–cell and cell–matrix interactions, growth, proliferation, differentiation, and inflammation. It is not surprising, therefore, that this protein is involved in the pathogenesis of many relevant human diseases, including cancer, fibrosis, chronic inflammation and scarring affecting many different tissues. The papers published in the literature have progressively increased in number during the last decades, testifying the great interest given to this protein by numerous researchers involved in many different clinical contexts. Considering the crucial role exerted by Gal-3 in many different clinical conditions, Gal-3 is emerging as a new diagnostic, prognostic biomarker and as a new promising therapeutic target. The current review aims to extensively examine the studies published so far on the role of Gal-3 in all the clinical conditions and diseases, listed in alphabetical order, where it was analyzed.

https://www.mdpi.com/1422-0067/19/2/379/pdf

Galectin-3: One Molecule for an Alphabet of Diseases, from A to Z.

Galectins are a family of widely expressed β-galactoside-binding lectins in metazoans. The 15 mammalian galectins have either one or two conserved carbohydrate recognition domains (CRDs), with galectin-3 being able to pentamerize; they form complexes that crosslink glycosylated ligands to form a dynamic lattice. The galectin lattice regulates the diffusion, compartmentalization and endocytosis of plasma membrane glycoproteins and glycolipids. The galectin lattice also regulates the selection, activation and arrest of T cells, receptor kinase signaling and the functionality of membrane receptors, including the glucagon receptor, glucose and amino acid transporters, cadherins and integrins. The affinity of transmembrane glycoproteins to the galectin lattice is proportional to the number and branching of their N-glycans; with branching being mediated by Golgi N-acetylglucosaminyltransferase-branching enzymes and the supply of UDP-GlcNAc through metabolite flux through the hexosamine biosynthesis pathway. The relative affinities of glycoproteins for the galectin lattice depend on the activities of the Golgi enzymes that generate the epitopes of their ligands and, thus, provide a means to analyze biological function of lectins and of the 'glycome' more broadly.

/pdf/the-galectin-lattice-at-a-glance-n38v37du82.pdf

The galectin lattice at a glance.

In addition to sperm cells, seminal fluid contains various small membranous vesicles. These include prostasomes, membrane vesicles secreted by prostate epithelial cells. Prostasomes have been proposed to perform a variety of functions, including modulation of (immune) cell activity within the female reproductive tract and stimulation of sperm motility and capacitation. How prostasomes mediate such diverse functions, however, remains unclear. In many studies, vesicles from the seminal plasma have been categorized collectively as a single population of prostasomes; in fact, they more likely represent a heterogeneous mixture of vesicles produced by different reproductive glands and secretory mechanisms. We here characterized membranous vesicles from seminal fluid obtained from vasectomized men, thereby excluding material from the testes or epididymides. Two distinct populations of vesicles with characteristic sizes (56 ± 13 nm vs. 105 ± 25 nm) but similar equilibrium buoyant density (∼1.15 g/ml) could be separated by using the distinct rates with which they floated into sucrose gradients. Both types of vesicle resembled exosomes in terms of their buoyant density, size, and the presence of the ubiquitous exosome marker CD9. The protein GLIPR2 was found to be specifically enriched in the lumen of the smaller vesicles, while annexin A1 was uniquely associated with the surface of the larger vesicles. Prostate stem-cell antigen (PSCA), a prostate-specific protein, was present on both populations, thereby confirming their origin. PSCA was, however, absent from membrane vesicles in the seminal fluid of some donors, indicating heterogeneity of prostasome characteristics between individuals.

Identification of Distinct Populations of Prostasomes That Differentially Express Prostate Stem Cell Antigen, Annexin A1 and GLIPR2 in Humans

The term 'prostasomes' is generally used to classify the extracellular vesicles (EVs) released into prostatic fluid by prostate epithelial cells. However, other epithelia within the male reproductive tract also release EVs that mix with 'true' prostasomes during semen emission or ejaculation. Prostasomes have been proposed to regulate the timing of sperm cell capacitation and induction of the acrosome reaction, as well as to stimulate sperm motility where all three are prerequisite processes for spermatozoa to attain fertilising capacity. Other proposed functions of prostasomes include interfering with the destruction of spermatozoa by immune cells within the female reproductive tract. On the other hand, it is unclear whether the distinct presumed functions are performed collectively by a single type of prostasome or by separate distinct sub-populations of EVs. Moreover, the exact molecular mechanisms through which prostasomes exert their functions have not been fully resolved. Besides their physiological functions, prostasomes produced by prostate tumour cells have been suggested to support prostate cancer spread development, and prostasomes in peripheral blood plasma may prove to be valuable biomarkers for prostate cancer.

https://rep.bioscientifica.com/downloadpdf/journals/rep/147/1/R1.pdf

Prostasomes: extracellular vesicles from the prostate

Extracellular vesicles (EVs) are membrane-bound complexes secreted from cells under both physiological and pathological conditions. They contain proteins, nucleic acids and lipids and act as messengers for cell–cell communication and signalling, particularly between immune cells. EV research is a rapidly evolving and expanding field, and it appears that all biological fluids contain very large numbers of EVs; they are produced from all cells that have been studied to date, and are known to have roles in several reproductive processes. This review analyses the evidence for the role of EVs throughout human reproduction, starting with the paternal and maternal gametes, followed by the establishment and continuation of successful pregnancies, with specific focus, where possible, on the interaction of EVs with the maternal immune system. Importantly, variations within the EV populations are identified in various reproductive disorders, such as pre-term labour and pre-eclampsia.

/pdf/extracellular-vesicles-and-reproduction-promotion-of-4cxgn3doqm.pdf

Extracellular vesicles and reproduction-promotion of successful pregnancy.

Galectin-3 is a β-galactoside-binding protein involved in immunomodulation, cell interactions, cancer progression, and pathogenesis of infectious organisms. We report the identification and characterization of galectin-3 in human semen. In the male reproductive tract, the ~30 kDa galectin-3 protein was identified in testis, epididymis, vas deferens, prostate, seminal vesicle, and sperm protein extracts. In seminal plasma, galectin-3 was identified in the soluble fraction and in prostasomes, cholesterol-rich, membranous vesicles that are secreted by the prostate and incorporated into seminal plasma during ejaculation. Two-dimensional immunoblot analysis of purified prostasomes identified five galectin-3 isoelectric variants with a pI range of 7.0 to 9.2. Affinity purification and tandem mass spectrometry of β-galactoside-binding proteins from prostasomes confirmed the presence of galectin-3 in prostasomes and identified a truncated galectin-3 variant. The intact galectin-3 molecule contains a carbohydrate recognition domain and a non-lectin domain that interacts with protein and lipid moieties. The identification of a monovalent galectin-3 fragment with conserved carbohydrate-binding activity indicates the functional relevance of this truncation and suggests a regulatory mechanism for galectin-3 in prostasomes. Surface biotinylation studies suggested that galectin-3 and the truncated galectin-3 variant are localized to the prostasome surface. Prostasomes are proposed to function in immunosuppression and regulation of sperm function in the female reproductive tract, are implicated in facilitating sexually-transmitted infections, and are indicated in prostate cancer progression. Given the overlap in functional significance, the identification of galectin-3 in prostasomes lays the groundwork for future studies of prostasomes in reproduction, disease transmission, and cancer progression.

/pdf/galectin-3-is-associated-with-prostasomes-in-human-semen-hg603oc2v2.pdf

Galectin-3 is associated with prostasomes in human semen

BACKGROUND

Prostasomes are exosome-like vesicles that are secreted by the prostate and incorporated into semen during ejaculation. Human prostasomes are proposed to function in regulation of sperm function, immunosuppression, and prostate cancer progression. Previously, we identified galectin-3 on the surface of prostasomes. Galectin-3 is a β-galactoside binding protein involved in immunomodulation, cell interactions, and cancer progression, including prostate cancer. Functional characterization of galectin-3 in a given biological environment includes identification of its target glycoprotein ligands.



METHODS

Candidate galectin-3 ligands in prostasomes were identified by tandem mass spectrometry of proteins that co-purified with galectin-3 during lactose affinity chromatography. Immunochemical and biochemical methods were used to investigate the association of Mac-2 binding protein (M2BP) with prostasomes.



RESULTS

Proteins identified by tandem mass spectrometry included M2BP, CD26/dipeptidyl peptidase IV, prolactin-inducible protein (PIP), olfactomedin-4 (OLFM4), and semenogelins I and II (SgI and SgII). M2BP is a known galectin-3 ligand that was not previously described in prostasomes. M2BP protein bands were detected in the testis, epididymis, vas deferens, prostate, seminal vesicle, and sperm extracts. In seminal plasma, M2BP was identified in the soluble fraction and in purified prostasomes. Surface biotinylation and immunofluorescence studies indicated that M2BP is present on the prostasome surface and on sperm, respectively.



CONCLUSIONS

M2BP, CD26, PIP, OLFM4, and SgI and SgII are candidate glycoprotein ligands for galectin-3 in prostasomes. Given their overlap in functional significance with prostasomes and galectin-3, the identification of these glycoproteins as galectin-3 ligands in prostasomes lays the groundwork for future studies of prostasomes in reproduction and prostate cancer. Prostate 71:711–721, 2011. © 2010 Wiley-Liss, Inc.

Co‐purification of Mac‐2 binding protein with galectin‐3 and association with prostasomes in human semen

Galectins and their Role in Various Biological Processes

BACKGROUND

Galectin-3 is a multivalent carbohydrate-binding protein involved in cell adhesion, cell cycle control, immunomodulation, and cancer progression, including prostate cancer. Galectin-3 function is regulated by proteolytic cleavage that destroys galectin-3 multivalency while preserving carbohydrate-binding activity. In human semen, galectin-3 is present in seminal plasma and is also associated with prostasomes, exosome-like vesicles secreted by the prostate. In the current study, we characterized the proteolytic activity that cleaves galectin-3 in human seminal plasma.



METHODS

An in vitro assay was developed to investigate galectin-3 cleavage in seminal plasma. The effect of protease inhibitors, divalent ion chelators, and Zn2+ on the cleavage activity was determined. Proteases enriched from seminal plasma were tested for their ability to cleave galectin-3. Affinity purification and microsequence analysis were used to identify the cleavage site in galectin-3.



RESULTS

Galectin-3 was identified in human seminal plasma in an intact and truncated form. Gelatinases enriched from seminal plasma did not cleave galectin-3. Inhibitor studies indicated that the galectin-3 cleavage activity in seminal plasma is a Zn2+ sensitive, serine protease. Prostate specific antigen (PSA) was demonstrated to cleave galectin-3 between tyrosine107-glycine108 and produce a functionally active, monovalent lectin.



CONCLUSIONS

PSA is a chymotrypsin-like serine protease secreted by the prostatic epithelium and normally functions in liquefaction of semen following ejaculation. Furthermore, PSA is implicated in the promotion of localized prostate tumors and bone metastases by its roles in immunomodulation, invasion, and apoptosis. Our results indicate that PSA regulates galectin-3 in human semen and may regulate galectin-3 function during prostate cancer progression. Prostate 71: 197–208, 2011. © 2010 Wiley-Liss, Inc.

/pdf/galectin-3-is-a-substrate-for-prostate-specific-antigen-psa-4mg2zzrp9k.pdf

Galectin-3 is a substrate for prostate specific antigen (PSA) in human seminal plasma.

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Galectin-3 is associated with prostasomes in human semen

Co‐purification of Mac‐2 binding protein with galectin‐3 and association with prostasomes in human semen

Galectins and their Role in Various Biological Processes

Galectin-3 is a substrate for prostate specific antigen (PSA) in human seminal plasma.