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1.
Am J Physiol Cell Physiol ; 322(5): C960-C966, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35385327

RESUMO

The syndecans are a family of transmembrane proteoglycans that are widespread in mammalian tissues. Located at the cell surface membrane, they contribute to modulating the composition of the extracellular matrix via glycosaminoglycan chains (GAGs) attached to their extracellular domains. Syndecans can interact with a variety of extracellular ligands through their core proteins and GAGs, and may also transmit signals through their transmembrane domain to regulate intracellular functions. These properties enable syndecan to modulate glycocalyx formation, epithelial cell-to-cell connections for cell barrier formation, and epithelial cell-lamina propria interactions in the colon epithelium, all of which are crucial for the homeostasis of this tissue. Inflammation induces structural alterations of the colon epithelium, and accumulating evidence suggests that syndecan expression might play important regulatory functions during inflammation. This review summarizes the possible roles of syndecans in maintaining tissue homeostasis in the colon epithelium, especially under inflammation.


Assuntos
Colo , Inflamação , Animais , Colo/metabolismo , Epitélio/metabolismo , Homeostase , Mamíferos/metabolismo , Sindecanas/metabolismo
2.
Int J Mol Sci ; 23(6)2022 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-35328830

RESUMO

Early diagnosis of Alzheimer's disease (AD) is of paramount importance in preserving the patient's mental and physical health in a fairly manageable condition for a longer period. Reliable AD detection requires novel biomarkers indicating central nervous system (CNS) degeneration in the periphery. Members of the syndecan family of transmembrane proteoglycans are emerging new targets in inflammatory and neurodegenerative disorders. Reviewing the growing scientific evidence on the involvement of syndecans in the pathomechanism of AD, we analyzed the expression of the neuronal syndecan, syndecan-3 (SDC3), in experimental models of neurodegeneration. Initial in vitro studies showed that prolonged treatment of tumor necrosis factor-alpha (TNF-α) increases SDC3 expression in model neuronal and brain microvascular endothelial cell lines. In vivo studies revealed elevated concentrations of TNF-α in the blood and brain of APPSWE-Tau transgenic mice, along with increased SDC3 concentration in the brain and the liver. Primary brain endothelial cells and peripheral blood monocytes isolated from APPSWE-Tau mice exhibited increased SDC3 expression than wild-type controls. SDC3 expression of blood-derived monocytes showed a positive correlation with amyloid plaque load in the brain, demonstrating that SDC3 on monocytes is a good indicator of amyloid pathology in the brain. Given the well-established role of blood tests, the SDC3 expression of monocytes could serve as a novel biomarker for early AD detection.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Biomarcadores , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Camundongos , Camundongos Transgênicos , Sindecana-3 , Sindecanas , Fator de Necrose Tumoral alfa
3.
APMIS ; 130(3): 155-168, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34939229

RESUMO

Sepsis manifests as a dysregulated immune response to infection, damaging organs. Skin has a critical role in protecting the body. In sepsis, skin wound healing is impaired. The mechanisms behind it have been poorly studied. In this study, suction blister wounds were induced on intact abdominal skin in 15 septic patients. A single blister wound was biopsied from each patient and from 10 healthy controls. Immunohistochemical staining of growth factors and extracellular matrix (ECM) proteins was performed. Significance (p < 0.05) of the differences was calculated. The following growth factors were overexpressed in the skin of septic patients compared with healthy controls: epithelial growth factor (intact epithelium p = 0.007, migrating epithelium p = 0.038), vascular epithelial growth factor (intact epithelium p < 0.001, migrating epithelium p = 0.011) and transforming growth factor beta (migrating epithelium p = 0.002). The expression of syndecan-1 was upregulated in the skin of septic patients compared with healthy controls (intact epithelium p = 0.048, migrating epithelium p = 0.028). The following ECM proteins had lower expression in the epithelium in septic patients than in healthy controls: tenascin-C (migrating epithelium p = 0.03) and laminin-332 (intact epithelium p = 0.036). In sepsis, growth factor and syndecan expression was enhanced, while ECM and basement membrane proteins were mostly depressed.


Assuntos
Proteínas da Matriz Extracelular/metabolismo , Matriz Extracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Pele/metabolismo , Cicatrização/fisiologia , Idoso , Estudos de Casos e Controles , Epitélio/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Sepse/metabolismo , Sindecanas/metabolismo , Tenascina/metabolismo , Regulação para Cima/fisiologia
4.
Med Sci (Paris) ; 37(12): 1101-1107, 2021 Dec.
Artigo em Francês | MEDLINE | ID: mdl-34928212

RESUMO

Exosomes are small extracellular vesicles derived from endosomal compartments. The molecular mechanisms supporting the biology of exosomes, from their biogenesis to their internalization by target cells, rely on 'dedicated' membrane proteins. These mechanisms of action need to be further clarified. This will help to better understand how exosome composition and heterogeneity are established. This would also help to rationalize their use as source of biomarkers and therapeutic tools. Here we discuss how syndecans and tetraspanins, two families of membrane scaffold proteins, cooperate to regulate different steps of exosome biology.


TITLE: Tétraspanines et syndécanes - Complices dans le « trafic ¼ des exosomes ? ABSTRACT: Les exosomes sont de petites vésicules extracellulaires qui sont produites dans des compartiments endosomaux. Les mécanismes moléculaires sur lesquels reposent la biologie des exosomes, de leur biogenèse à leur internalisation par les cellules cibles, font notamment appel à des protéines membranaires particulières. Ces mécanismes méritent d'être clarifiés, afin de mieux comprendre la complexité de la composition des exosomes et de rationaliser leur utilisation comme biomarqueurs ou comme outils thérapeutiques. Nous discutons ici comment les syndécanes et les tétraspanines, deux familles de protéines d'échafaudage, coopèrent pour réguler les différentes étapes de la biologie des exosomes.


Assuntos
Exossomos , Crime , Sindecanas , Tetraspaninas
5.
Exp Eye Res ; 213: 108846, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34801534

RESUMO

PURPOSE: Diabetic retinopathy is a vision-threatening complication of diabetes characterized by endothelial injury and vascular dysfunction. The loss of the endothelial glycocalyx, a dynamic layer lining all endothelial cells, contributes to several microvascular pathologies, including an increase in vascular permeability, leukocyte plugging, and capillary occlusion, and may drive the progression of retinopathy. Previously, a significant decrease in glycocalyx thickness has been observed in diabetic retinas. However, the effects of diabetes on specific components of the retinal glycocalyx have not yet been studied. Therefore, the aim of our study was to investigate changes in synthesis, expression, and shedding of retinal glycocalyx components induced by hyperglycemia, which could provide a novel therapeutic target for diabetic retinopathy. METHODS: Primary rat retinal microvascular endothelial cells (RRMECs) were grown under normal glucose (5 mM) or high-glucose (25 mM) conditions for 6 days. The mRNA and protein levels of the glycocalyx components were examined using qRT-PCR and Western blot analysis, respectively. Further, mass spectrometry was used to analyze protein intensities of core proteins. In addition, the streptozotocin-induced Type 1 diabetic rat model was used to study changes in the expression of the retinal glycocalyx in vivo. The shedding of the glycocalyx was studied in both culture medium and in plasma using Western blot analysis. RESULTS: A significant increase in the shedding of syndecan-1 and CD44 was observed both in vitro and in vivo under high-glucose conditions. The mRNA levels of syndecan-3 were significantly lower in the RRMECs grown under high glucose conditions, whereas those of syndecan-1, syndecan-2, syndecan-4, glypican-1, glypican-3, and CD44 were significantly higher. The protein expression of syndecan-3 and glypican-1 in RRMECs was reduced considerably following exposure to high glucose, whereas that of syndecan-1 and CD44 increased significantly. In addition, mass spectrometry data also suggests a significant increase in syndecan-4 and a significant decrease in glypican-3 protein levels with high glucose stimulation. In vivo, our data also suggest a significant decrease in the mRNA transcripts of syndecan-3 and an increase in mRNA levels of glypican-1 and CD44 in the retinas of diabetic rats. The diabetic rats exhibited a significant reduction in the retinal expression of syndecan-3 and CD44. However, the expression of syndecan-1 and glypican-1 increased significantly in the diabetic retina. CONCLUSIONS: One of the main findings of our study was the considerable diversity of glucose-induced changes in expression and shedding of various components of endothelial glycocalyx, for example, increased endothelial and retinal syndecan-1, but decreased endothelial and retinal syndecan-3. This indicates that the reported decrease in the retinal glycocalyx in diabetes in not a result of a non-specific shedding mechanism. Moreover, mRNA measurements indicated a similar diversity, with increases in endothelial and/or retinal levels of syndecan-1, glypican-1, and CD44, but a decrease for syndecan-3, with these increases in mRNA potentially a compensatory reaction to the overall loss of glycocalyx.


Assuntos
Retinopatia Diabética/metabolismo , Glicocálix/metabolismo , Hiperglicemia/metabolismo , Retina/metabolismo , Animais , Glicemia/metabolismo , Western Blotting , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Ensaio de Imunoadsorção Enzimática , Glucose/farmacologia , Glipicanas/metabolismo , Receptores de Hialuronatos/metabolismo , Insulina/sangue , Masculino , Espectrometria de Massas , RNA Mensageiro/genética , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Vasos Retinianos/citologia , Sindecanas/metabolismo
6.
Biomaterials ; 277: 121113, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34492582

RESUMO

Biomaterial based strategies have been widely explored to preserve and restore the juvenile phenotype of cells of the nucleus pulposus (NP) in degenerated intervertebral discs (IVD). With aging and maturation, NP cells lose their ability to produce necessary extracellular matrix and proteoglycans, accelerating disc degeneration. Previous studies have shown that integrin or syndecan binding peptide motifs from laminin can induce NP cells from degenerative human discs to re-express juvenile NP-specific cell phenotype and biosynthetic activity. Here, we engineered alginate hydrogels to present integrin- and syndecan-binding peptides alone or in combination (cyclic RGD and AG73, respectively) to introduce bioactive features into the alginate gels. We demonstrated human NP cells cultured upon and within alginate hydrogels presented with cRGD and AG73 peptides exhibited higher cell viability, biosynthetic activity, and NP-specific protein expression over alginate alone. Moreover, the combination of the two peptide motifs elicited markers of the NP-specific cell phenotype, including N-Cadherin, despite differences in cell morphology and multicellular cluster formation between 2D and 3D cultures. These results represent a promising step toward understanding how distinct adhesive peptides can be combined to guide NP cell fate. In the future, these insights may be useful to rationally design hydrogels for NP cell-transplantation based therapies for IVD degeneration.


Assuntos
Degeneração do Disco Intervertebral , Disco Intervertebral , Núcleo Pulposo , Alginatos , Humanos , Hidrogéis , Integrinas , Peptídeos , Fenótipo , Sindecanas
7.
Cells ; 10(7)2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34359876

RESUMO

The lung extracellular matrix (ECM) plays a key role in the normal architecture of the lung, from embryonic lung development to mechanical stability and elastic recoil of the breathing adult lung. The lung ECM can modulate the biophysical environment of cells through ECM stiffness, porosity, topography and insolubility. In a reciprocal interaction, lung ECM dynamics result from the synthesis, degradation and organization of ECM components by the surrounding structural and immune cells. Repeated lung injury and repair can trigger a vicious cycle of aberrant ECM protein deposition, accompanied by elevated ECM stiffness, which has a lasting effect on cell and tissue function. The processes governing the resolution of injury repair are regulated by several pathways; however, in chronic lung diseases such as asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary disease (IPF) these processes are compromised, resulting in impaired cell function and ECM remodeling. Current estimates show that more than 60% of the human coding transcripts are regulated by miRNAs. miRNAs are small non-coding RNAs that regulate gene expressions and modulate cellular functions. This review is focused on the current knowledge of miRNAs in regulating ECM synthesis, degradation and topography by cells and their dysregulation in asthma, COPD and IPF.


Assuntos
Asma/genética , Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Fibrose Pulmonar Idiopática/genética , MicroRNAs/genética , Doença Pulmonar Obstrutiva Crônica/genética , Asma/metabolismo , Asma/patologia , Colágeno/genética , Colágeno/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Matriz Extracelular/química , Fibroblastos/patologia , Fibronectinas/genética , Fibronectinas/metabolismo , Regulação da Expressão Gênica , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Laminina/genética , Laminina/metabolismo , Pulmão/metabolismo , Pulmão/patologia , MicroRNAs/classificação , MicroRNAs/metabolismo , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Transdução de Sinais , Sindecanas/genética , Sindecanas/metabolismo , Versicanas/genética , Versicanas/metabolismo
8.
Dev Growth Differ ; 63(6): 295-305, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34324711

RESUMO

The Drosophila female germline stem cell (GSC) niche provides an excellent model for understanding the stem cell niche in vivo. The GSC niche is composed of stromal cells that provide growth factors for the maintenance of GSCs and the associated extracellular matrix (ECM). Although the function of stromal cells/growth factors has been well studied, the function of the ECM in the GSC niche is largely unknown. In this study, we investigated the function of syndecan and perlecan, molecules of the heparan sulfate proteoglycan (HSPG) family, as the main constituents of the ECM. We found that both of these genes were expressed in niche stromal cells, and knockdown of them in stromal cells decreased GSC number, indicating that these genes are important niche components. Interestingly, our genetic analysis revealed that the effects of syndecan and perlecan on the maintenance of GSC were distinct. While the knockdown of perlecan in the GSC niche increased the number of cystoblasts, a phenotype suggestive of delayed differentiation of GSCs, the same was not true in the context of syndecan. Notably, the overexpression of syndecan and perlecan did not cause an expansion of the GSC niche, opposing the results reported in the context of glypican, another HSPG gene. Altogether, our data suggest that HSPG genes contribute to the maintenance of GSCs through multiple mechanisms, such as the control of signal transduction, and ligand distribution/stabilization. Therefore, our study paves the way for a deeper understanding of the ECM functions in the stem cell niche.


Assuntos
Drosophila , Proteoglicanas de Heparan Sulfato , Animais , Células Germinativas , Proteoglicanas de Heparan Sulfato/genética , Células-Tronco , Sindecanas/genética
9.
Ginekol Pol ; 92(11): 745-752, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34263915

RESUMO

OBJECTIVES: Concentrations of soluble ICAM-2, -3, -4 and syndecan-1 and -4 have not yet been marked in the peritoneal fluid of women with endometriosis. The aim of the study was to determine whether these molecules can participate in formation and development of endometriosis. MATERIAL AND METHODS: The study comprised of 80 women at the proliferative phase of the menstrual cycle, aged 21 to 49 years (mean age 31. 3 ± 6. 7 years) undergoing laparoscopy, to determine the causes of primary infertility and to confirm or exclude endometriosis. The study group consisted of 60 women with endometriosis in the pelvis as confirmed by laparoscopy and histopathology. The reference group consisted of 20 women in whom no endometriosis. Concentrations of selected sICAM and syndecans in the peritoneal fluid were determined with the use of ELISA method. RESULTS: Decreased concentrations of sICAM-2 and increased concentrations of sICAM-3, sICAM-4 and syndnecan-1 and -4 were observed in the peritoneal fluid of women with endometriosis and compared with concentrations of this parameter in the reference group (p < 0.0001). Additionally, negative correlation was found between the concentrations of sICAM-3 and sICAM-2 among women with endometriosis. There was no statistically significant correlation between the concentration of sICAM-2 and sICAM-4, sICAM-3 and sICAM-4 and syndecan-1 and syndecan-4 in the examined women. CONCLUSIONS: Changes in concentrations of all the evaluated molecules were observed in the peritoneal fluid in women suffering from endometriosis. Since they have a role in regulation of the immune response, in angiogenesis and apoptosis of the endometrial cells.


Assuntos
Antígenos CD/química , Moléculas de Adesão Celular/química , Endometriose , Sindecanas , Adulto , Líquido Ascítico , Endometriose/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Sindecanas/química , Adulto Jovem
10.
J Cell Biol ; 220(9)2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34213535

RESUMO

The extracellular matrix has emerged as an active component of chemical synapses regulating synaptic formation, maintenance, and homeostasis. The heparan sulfate proteoglycan (HSPG) syndecans are known to regulate cellular and axonal migration in the brain. They are also enriched at synapses, but their synaptic functions remain more elusive. Here, we show that SDN-1, the sole orthologue of syndecan in C. elegans, is absolutely required for the synaptic clustering of homomeric α7-like acetylcholine receptors (AChRs) and regulates the synaptic content of heteromeric AChRs. SDN-1 is concentrated at neuromuscular junctions (NMJs) by the neurally secreted synaptic organizer Ce-Punctin/MADD-4, which also activates the transmembrane netrin receptor DCC. Those cooperatively recruit the FARP and CASK orthologues that localize α7-like-AChRs at cholinergic NMJs through physical interactions. Therefore, SDN-1 stands at the core of the cholinergic synapse organization by bridging the extracellular synaptic determinants to the intracellular synaptic scaffold that controls the postsynaptic receptor content.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Proteínas do Tecido Nervoso/metabolismo , Junção Neuromuscular/metabolismo , Receptores Colinérgicos/metabolismo , Sinapses/metabolismo , Sindecanas/metabolismo , Acetilcolina/metabolismo , /metabolismo , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Receptor DCC/genética , Receptor DCC/metabolismo , Matriz Extracelular/química , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica , Guanilato Quinases/genética , Guanilato Quinases/metabolismo , Proteínas do Tecido Nervoso/genética , Junção Neuromuscular/ultraestrutura , Neurônios/citologia , Neurônios/metabolismo , Receptores Colinérgicos/genética , Sinapses/ultraestrutura , Transmissão Sináptica/genética , Sindecanas/genética
11.
Eur J Med Chem ; 223: 113601, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34153575

RESUMO

Syntenin stimulates exosome production and its expression is upregulated in many cancers and implicated in the spread of metastatic tumor. These effects are supported by syntenin PDZ domains interacting with syndecans. We therefore aimed to develop, through a fragment-based drug design approach, novel inhibitors targeting syntenin-syndecan interactions. We describe here the optimization of a fragment, 'hit' C58, identified by in vitro screening of a PDZ-focused fragment library, which binds specifically to the syntenin-PDZ2 domain at the same binding site as the syndecan-2 peptide. X-ray crystallographic structures and computational docking were used to guide our optimization process and lead to compounds 45 and 57 (IC50 = 33 µM and 47 µM; respectively), two representatives of syntenin-syndecan interactions inhibitors, that selectively affect the syntenin-exosome release. These findings demonstrate that it is possible to identify small molecules inhibiting syntenin-syndecan interaction and exosome release that may be useful for cancer therapy.


Assuntos
Aminoácidos/farmacologia , Antineoplásicos/farmacologia , Derivados de Benzeno/farmacologia , Exossomos/metabolismo , Sinteninas/metabolismo , Aminoácidos/síntese química , Aminoácidos/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Derivados de Benzeno/síntese química , Derivados de Benzeno/metabolismo , Desenho de Fármacos , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Molecular , Domínios PDZ , Ligação Proteica/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Sindecanas/metabolismo , Sinteninas/química
12.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069441

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel emerging pathogen causing an unprecedented pandemic in 21st century medicine. Due to the significant health and economic burden of the current SARS-CoV-2 outbreak, there is a huge unmet medical need for novel interventions effectively blocking SARS-CoV-2 infection. Unknown details of SARS-CoV-2 cellular biology hamper the development of potent and highly specific SARS-CoV-2 therapeutics. Angiotensin-converting enzyme-2 (ACE2) has been reported to be the primary receptor for SARS-CoV-2 cellular entry. However, emerging scientific evidence suggests the involvement of additional membrane proteins, such as heparan sulfate proteoglycans, in SARS-CoV-2 internalization. Here, we report that syndecans, the evolutionarily conserved family of transmembrane proteoglycans, facilitate the cellular entry of SARS-CoV-2. Among syndecans, the lung abundant syndecan-4 was the most efficient in mediating SARS-CoV-2 uptake. The S1 subunit of the SARS-CoV-2 spike protein plays a dominant role in the virus's interactions with syndecans. Besides the polyanionic heparan sulfate chains, other parts of the syndecan ectodomain, such as the cell-binding domain, also contribute to the interaction with SARS-CoV-2. During virus internalization, syndecans colocalize with ACE2, suggesting a jointly shared internalization pathway. Both ACE2 and syndecan inhibitors exhibited significant efficacy in reducing the cellular entry of SARS-CoV-2, thus supporting the complex nature of internalization. Data obtained on syndecan specific in vitro assays present syndecans as novel cellular targets of SARS-CoV-2 and offer molecularly precise yet simple strategies to overcome the complex nature of SARS-CoV-2 infection.


Assuntos
COVID-19/metabolismo , Receptores de Coronavírus/metabolismo , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/metabolismo , Sindecanas/metabolismo , Internalização do Vírus , Amilorida/farmacologia , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , COVID-19/virologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Bloqueadores do Canal de Sódio Epitelial/farmacologia , Humanos , Peptídeos/farmacologia , Domínios Proteicos , SARS-CoV-2/metabolismo , Sindecana-4/antagonistas & inibidores , Sindecana-4/metabolismo , Sindecanas/antagonistas & inibidores
13.
Genetics ; 218(4)2021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-33983408

RESUMO

Heparan sulfate (HS) proteoglycans contribute to the structural organization of various neurochemical synapses. Depending on the system, their role involves either the core protein or the glycosaminoglycan chains. These linear sugar chains are extensively modified by HS modification enzymes, resulting in highly diverse molecules. Specific modifications of glycosaminoglycan chains may thus contribute to a sugar code involved in synapse specificity. Caenorhabditis elegans is particularly useful to address this question because of the low level of genomic redundancy of these enzymes, as opposed to mammals. Here, we systematically mutated the genes encoding HS modification enzymes in C. elegans and analyzed their impact on excitatory and inhibitory neuromuscular junctions (NMJs). Using single chain antibodies that recognize different HS modification patterns, we show in vivo that these two HS epitopes are carried by the SDN-1 core protein, the unique C. elegans syndecan ortholog, at NMJs. Intriguingly, these antibodies differentially bind to excitatory and inhibitory synapses, implying unique HS modification patterns at different NMJs. Moreover, while most enzymes are individually dispensable for proper organization of NMJs, we show that 3-O-sulfation of SDN-1 is required to maintain wild-type levels of the extracellular matrix protein MADD-4/Punctin, a central synaptic organizer that defines the identity of excitatory and inhibitory synaptic domains at the plasma membrane of muscle cells.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Heparitina Sulfato/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Junção Neuromuscular/metabolismo , Processamento de Proteína Pós-Traducional , Animais , Caenorhabditis elegans , Estabilidade Proteica , Sindecanas/metabolismo
14.
J Mol Graph Model ; 106: 107938, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34020229

RESUMO

Syndecans (SDCs) are a family of four members of integral membrane proteins, which play important roles in cell-cell interactions. Dimerization/oligomerization generated by transmembrane domains (TMDs) appears to crucially regulate several functional behaviors of all syndecan members. The different levels of protein-protein interactions mediated by Syndecan TMDs may lead to a rather complicated function of Syndecans. The molecular mechanism of the different dimerization tendencies in each type of SDCs remains unclear. Here, the self-assembly process of syndecan TMD homodimers and heterodimers was studied in molecular details by molecular dynamics simulations. Our computational results showed that the SDC2 forms the most stable homodimer, which is consistent with previous experimental results. Detailed analysis suggests that instead of the conserved dimerizing motif G8XXXG12 in all four SDCs involved in homo- and hetero-dimerization of SDCs. The different locations of GXXXA motif affect the stability of SDC dimers. In addition, we found that A3XXXA7 can stabilize the dimerization, making the dimer of SDC2 the most stable among these SDC dimers. Our results shed light on the complex effect of multiple dimerizing motifs on the dimerization of transmembrane domains.


Assuntos
Sindecanas , Sequência de Aminoácidos , Dimerização , Domínios Proteicos , Estrutura Terciária de Proteína
15.
Biomolecules ; 11(3)2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33669066

RESUMO

Pancreatic Ductal Adenocarcinoma (PDAC) is a fatal disease with poor prognosis because patients rarely express symptoms in initial stages, which prevents early detection and diagnosis. Syndecans, a subfamily of proteoglycans, are involved in many physiological processes including cell proliferation, adhesion, and migration. Syndecans are physiologically found in many cell types and their interactions with other macromolecules enhance many pathways. In particular, extracellular matrix components, growth factors, and integrins collect the majority of syndecans associations acting as biochemical, physical, and mechanical transducers. Syndecans are transmembrane glycoproteins, but occasionally their extracellular domain can be released from the cell surface by the action of matrix metalloproteinases, converting them into soluble molecules that are capable of binding distant molecules such as extracellular matrix (ECM) components, growth factor receptors, and integrins from other cells. In this review, we explore the role of syndecans in tumorigenesis as well as their potential as therapeutic targets. Finally, this work reviews the contribution of syndecan-1 and syndecan-2 in PDAC progression and illustrates its potential to be targeted in future treatments for this devastating disease.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , Sindecanas/metabolismo , Animais , Matriz Extracelular/metabolismo , Humanos , Proteoglicanas/metabolismo , Transdução de Sinais/fisiologia
16.
Cytokine ; 142: 155503, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33781652

RESUMO

The role of glycosaminoglycans on the surface of immune cells has so far been less studied compared to their participation in inflammatory responses as members of the endothelium and the extracellular matrix. In this study we have therefore investigated if glycosaminoglycans on immune cells act in concert with GPC receptors (i.e. both being cis-located on leukocytes) in chemokine-induced leukocyte mobilisation. For this purpose, freshly-prepared human neutrophils and monocytes were treated with heparinase III or chondroitinase ABC to digest heparan sulfate -chains or chondroitin sulfate-chains, respectively, from the leukocyte surfaces. Subsequent analysis of CXCL8- and CCL2-induced chemotaxis revealed that leukocyte migration was strongly reduced after eliminating heparan sulfate from the surface of neutrophils and monocytes. In the case of monocytes, an additional dependence of CCL2-induced chemotaxis on chondroitin sulfate was observed. We compared these results with the effect on chemotaxis of a heparan sulfate masking antibody and obtained similarly reduced migration. Following our findings, we postulate that glycosaminoglycans located on target leukocytes act synergistically with GPC receptors on immune cell migration, which is further influenced by glycosaminoglycans located on the inflamed tissue (i.e. trans with respect to the immune cell/GPC receptor). Both glycosaminoglycan localization sites seem to be important during inflammatory processes and could potentially be tackled in chemokine-related diseases.


Assuntos
Movimento Celular , Quimiocina CCL2/farmacologia , Glicosaminoglicanos/metabolismo , Interleucina-8/farmacologia , Monócitos/metabolismo , Neutrófilos/metabolismo , Animais , Movimento Celular/efeitos dos fármacos , Condroitinases e Condroitina Liases/metabolismo , Feminino , Glipicanas/genética , Glipicanas/metabolismo , Heparina Liase/metabolismo , Humanos , Monócitos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Suínos , Sindecanas/genética , Sindecanas/metabolismo , Migração Transendotelial e Transepitelial/efeitos dos fármacos
17.
Open Biol ; 11(2): 200377, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33561383

RESUMO

The syndecans are the major family of transmembrane proteoglycans, usually bearing multiple heparan sulfate chains. They are present on virtually all nucleated cells of vertebrates and are also present in invertebrates, indicative of a long evolutionary history. Genetic models in both vertebrates and invertebrates have shown that syndecans link to the actin cytoskeleton and can fine-tune cell adhesion, migration, junction formation, polarity and differentiation. Although often associated as co-receptors with other classes of receptors (e.g. integrins, growth factor and morphogen receptors), syndecans can nonetheless signal to the cytoplasm in discrete ways. Syndecan expression levels are upregulated in development, tissue repair and an array of human diseases, which has led to the increased appreciation that they may be important in pathogenesis not only as diagnostic or prognostic agents, but also as potential targets. Here, their functions in development and inflammatory diseases are summarized, including their potential roles as conduits for viral pathogen entry into cells.


Assuntos
Sindecanas/metabolismo , Animais , Regulação da Expressão Gênica no Desenvolvimento , Heparitina Sulfato/metabolismo , Humanos , Doenças do Sistema Imunitário/metabolismo , Transdução de Sinais , Sindecanas/química
18.
Cancer Treat Res Commun ; 27: 100312, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33485180

RESUMO

While our understanding of tumors and how to treat them has advanced significantly since the days of Aminopterin and the radical mastectomy, cancer remains among the leading causes of death worldwide. Despite innumerable advancements in medical technology the non-static and highly heterogeneous nature of a tumor can make characterization and treatment exceedingly difficult. Because of this complexity, the identification of new cellular constituents that can be used for diagnostic, prognostic, and therapeutic purposes is crucial in improving patient outcomes worldwide. Growing evidence has demonstrated that among the myriad of changes seen in cancer cells, the Syndecan family of proteins has been observed to undergo drastic alterations in expression. Syndecans are transmembrane heparan sulfate proteoglycans that are responsible for cell signaling, proliferation, and adhesion, and many studies have shed light on their unique involvement in both tumor progression and suppression. This review seeks to discuss Syndecan expression levels in various cancers, whether they make reliable biomarkers for detection and prognosis, and whether they may be viable targets for future cancer therapies. The conclusions drawn from the literature reviewed in this article indicate that changes in expression of Syndecan protein can have profound effects on tumor size, metastatic capability, and overall patient survival rate. Further, while data regarding the therapeutic targeting of Syndecan proteins is sparse, the available literature does demonstrate promise for their use in cancer treatment going forward.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias/terapia , Sindecanas/metabolismo , Animais , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/sangue , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Imunoterapia Adotiva/métodos , Maitansina/análogos & derivados , Maitansina/farmacologia , Maitansina/uso terapêutico , Camundongos , Neoplasias/diagnóstico , Neoplasias/mortalidade , Neoplasias/patologia , Prognóstico , Intervalo Livre de Progressão , Receptores de Antígenos Quiméricos , Taxa de Sobrevida , Sindecanas/antagonistas & inibidores , Sindecanas/sangue , Ensaios Antitumorais Modelo de Xenoenxerto
19.
J Biomed Mater Res A ; 109(3): 313-325, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32490581

RESUMO

We have engineered biomaterials that display nanoclusters of ligands that bind both integrin and syndecan-4 cell receptors. These surfaces regulate cell behaviors under static conditions including adhesion, spreading, actin stress fiber formation, and migration. The syndecan-4 receptors are also critical mediators of cellular mechanotransduction. In this contribution we assess whether this novel class of materials can regulate the response of cells to applied mechanical stimulation, using the shear stress imparted by laminar fluid flow as a model stimulus. Specifically, we assess endothelial cell detachment due to flow, cell alignment due to flow, and cell adhesion from the flowing fluid. A high degree of cell retention was observed on surfaces containing integrin-binding ligands or a mixed population of integrin- and syndecan-binding ligands. However, the presence of both ligand types was necessary for the cells to align in the direction of flow. These results imply that integrin engagement is necessary for adhesion strength, but engagement of both receptor types aids in appropriate mechanotransduction. Additionally, it was found that surfaces functionalized with both ligand types were able to scavenge a larger number of cells from flow, and to do so at a faster rate, compared to surfaces functionalized with only integrin- or syndecan-binding ligands. These results show that interfaces functionalized with both integrin- and syndecan-binding ligands regulate a significant range of biophysical cell behaviors in response to shear stress.


Assuntos
Materiais Biocompatíveis/metabolismo , Adesão Celular , Integrinas/metabolismo , Sindecanas/metabolismo , Materiais Biocompatíveis/química , Células Endoteliais da Veia Umbilical Humana , Humanos , Ligantes , Mecanotransdução Celular , Estresse Mecânico
20.
Anat Rec (Hoboken) ; 304(3): 559-569, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32602655

RESUMO

Mandibular condylar cartilage is a representative secondary cartilage, differing from primary cartilage in various ways. Syndecan is a cell-surface heparan sulfate proteoglycan and speculated to be involved in chondrogenesis and osteogenesis. This study aimed to investigate the expression patterns of the syndecan family in the developing mouse mandibular condylar cartilage. At embryonic day (E)13.0 and E14.0, syndecan-1 and -2 mRNAs were expressed in the mesenchymal cell condensation of the condylar anlage. When condylar cartilage was formed at E15.0, syndecan-1 mRNA was expressed in the embryonic zone, wherein the mesenchymal cell condensation is located. Syndecan-2 mRNA was mainly expressed in the perichondrium. At E16.0, syndecan-1 was expressed from fibrous to flattened cell zones and syndecans-2 was expressed in the lower hypertrophic cell zone. Syndecan-3 mRNA was expressed in the condylar anlage at E13.0 and E13.5 but was not expressed in the condylar cartilage at E15.0. It was later expressed in the lower hypertrophic cell zone at E16.0. Syndecan-4 mRNA was expressed in the condylar anlage at E14.0 and the condylar cartilage at E15.0 and E16.0. These findings indicated that syndecans-1 and -2 could be involved in the formation from mesenchymal cell condensation to condylar cartilage. The different expression patterns of the syndecan family in the condylar and limb bud cartilage suggest the functional heterogeneity of chondrocytes in the primary and secondary cartilage.


Assuntos
Cartilagem/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Côndilo Mandibular/metabolismo , Sindecanas/metabolismo , Animais , Cartilagem/embriologia , Condrócitos/metabolismo , Hibridização In Situ , Côndilo Mandibular/embriologia , Camundongos , Sindecanas/genética
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