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Map of the integrin-binding region of osteopontin. nOPN; Nterminal fragment of thrombin-cleaved, osteopontin. fOPN; full length osteopontin. Asparatic acid residues replaced with alanine are shown in gray. RGD sequence recognized by integrins avh6, avh3, avh5 anda5h1 is in a bold type. SVVYGLR sequence recognized by integrin a9h1 is in underlined italic. MMP-3 or MMP-7 cleaves between Gly and Leu (arrow head) within the SVVYGLR. Thrombin cleavage site is indicated by an arrowhead.
Source publication
![Fig. 1. Affinity chromatography. [ 35 S]methionine-and [ 35...](profile/Yasuyuki-Yokosaki/publication/7739705/figure/fig1/AS:394516696715269@1471071518624/Affinity-chromatography-35-Smethionine-and-35-Scycteinelabeled-secreted-avh6-was_Q320.jpg)
The extracellular matrix protein, osteopontin, is a ligand for several members of the integrin family, including alpha5beta1, alphavbeta3, alphavbeta5 and alpha9beta1. Osteopontin is a substrate for a number of extracellular proteases, including thrombin and the metalloproteases MMP-3 and MMP-7, which cleave osteopontin at sites close to or within...
Contexts in source publication
Context 1
... and a5h1, in comparison with a9h1 that recognizes a non-RGD site ( Yokosaki et al., 1999). The structure of the RGD-containing region in osteopontin was modified by substitution of two upstream asparatic acid residues by alanine (D154A and D157A) and by substitution of a downstream tyrosine residue that is critical for binding of a9h1 (Y165A) (Fig. 5) (Yokosaki et al., 1999). To examine the role of individual integrins in binding to each mutant, we performed adhesion assays in the presence of blocking antibodies to each of the other integrins present in our various cell lines. Thus, binding of integrin avh3 was observed as adhesion of h3-transfected SW480 cells in the presence of ...
Context 2
... integrin mediated adhesion to osteopontin appeared to be affected by conformational changes close to or within the integrin binding site (Fig. 5), we next compared adhesion mediated by each integrin to full length osteopontin (fOPN) and recombinant forms mim- icking two naturally occurring cleavage forms that are produced by cleavage by proteases, MMP-3 or MMP-7 (nOPN-dLR), or thrombin (the nOPN form used above) (Fig. 5). The MMP-3, 7-cleaved form (nOPN-dLR) was made by deletion ...
Context 3
... conformational changes close to or within the integrin binding site (Fig. 5), we next compared adhesion mediated by each integrin to full length osteopontin (fOPN) and recombinant forms mim- icking two naturally occurring cleavage forms that are produced by cleavage by proteases, MMP-3 or MMP-7 (nOPN-dLR), or thrombin (the nOPN form used above) (Fig. 5). The MMP-3, 7-cleaved form (nOPN-dLR) was made by deletion of 2 residues, LR, of nOPN. fOPN was generated from full length cDNA. Integrins avh6, avh3 or avh5 each bound equally well to nOPN, nOPN-dLR and fOPN, indicating that these 2 cleavages do not influence their binding to osteopontin. In contrast, a5h1- mediated adhesion was ...
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Citations
... Consequently, VEGF's function is mimicked by Tat, upregulating angiogenesis, and the expression of αvβ3 and α5β1 integrin and endothelial cell (EC) adhesion [67,68]. These can further bind to angiogenic factors that play a role in decidualization [69]. It was shown that both endothelial nitric oxide synthase (eNos) expression and endothelium-dependent vasorelaxation were reduced by the Tat protein. ...
Purpose of Review
The primary goal of this review article was to determine whether the three RAAS-associated SNPs, Renin-rs16853055, AGT-rs3789678 and ACE-rs4305 are genetically linked to the development of hypertension in preeclampsia. The secondary goal was to establish if there was a link between these SNPs and HIV infection.
Recent Findings
There is a paucity of findings related to the aforementioned SNPs and preeclampsia. There are no recent findings on the rs16853055 renin polymorphism. The rs3789678 angiotensinogen polymorphism correlated significantly with gestational hypertension. The rs4305 ACE polymorphism showed no significant association with the development of pregnancy-induced hypertension.
Summary
There are conflicting findings when determining the relationship between ethnicity and the predisposition of preeclampsia and hypertension in relation to the discussed RAAS-associated SNPs. To date, the association between RAAS-associated SNPs and preeclamptic women co-morbid with HIV in South Africa has revealed that certain alleles of the AGT gene are more prominent in HIV-infected PE compared to normotensive pregnant HIV-infected women.
... Integrins are the most important cell surface receptor of OPN; the RGD domain allows interaction with several integrins, including α v (β 1 , β 3 , β 5 , β 6 , β 8 ) and (α 5, α 8 ) β 1 and/ or α IIb β 3 ; the SVVYGLR domain binds to α 4 β 1 , α 4 β 7 , and α 9 β; and α 4 β 1 is suspected to bind to the ELVTDFTDLPAT domain [22,23]. Additionally, CD44 is another important receptor of OPN, and OPN has also been shown to interact with CD44, specifically CD44v3 and CD44v6-7 variants, via the C-terminal calcium domain [24][25][26]. ...
Osteopontin (OPN) is a multifunctional phosphorylated protein that is involved in physiological and pathological events. Emerging evidence suggests that OPN also plays a critical role in the pathogenesis of respiratory diseases. OPN can be produced and secreted by various cell types in lungs and overexpression of OPN has been found in acute lung injury/acute respiratory distress syndrome (ALI/ARDS), pulmonary hypertension (PH), pulmonary fibrosis diseases, lung cancer, lung infection, chronic obstructive pulmonary disease (COPD), and asthma. OPN exerts diverse effects on the inflammatory response, immune cell activation, fibrosis and tissue remodeling, and tumorigenesis of these respiratory diseases, and genetic and pharmacological moudulation of OPN exerts therapeutic effects in the treatment of respiratory diseases. In this review, we summarize the recent evidence of multifaceted roles and underlying mechanisms of OPN in these respiratory diseases, and targeting OPN appears to be a potential therapeutic intervention for these diseases.
... The integrin family of receptors bind OPN's core RGD motif, and they are the main receptor class for OPN binding [7][8][9]. OPN binds the α V β 1 , α V β 3 , α V β 5 , α v β 6 , α 5 β 1 and α 8 β 1 integrins via the RGD sequence [8,86], whereas the α 4 β 1 and α 9 β 1 integrins bind OPN through its cryptic SVVYGLR sequence [59,60]. In contrast, integrin α X β 2 on myeloid leukocytes, and natural killer cells binds OPN through the negative charges on OPN independently of the RGD or SVVYGLR motifs [49,87]. ...
Osteopontin (OPN) is a multifunctional protein found in all vertebrates. OPN is expressed in many different cell types, and is consequently found in most tissues and physiological secretions. OPN is involved in a multitude of biological processes, such as activation and regulation of the immune system; biomineralization; tissue-transformative processes, including growth and development of the gut and brain; interaction with bacteria; and many more. OPN is found in the highest concentrations in milk, where it is believed to initiate and regulate developmental, immunological and physiological processes in infants who consume milk. Processes for the isolation of bovine OPN for use in infant formula have been developed, and in recent years, many studies have investigated the effects of the intake of milk OPN. The purpose of this article is to review and compare existing knowledge about the structure and function of milk OPN, with a particular focus on the effects of milk OPN on human health and disease.
... It is also cleaved by various proteases, including thrombin, matrix metalloproteinase (MMP)-3, MMP-7, cathepsin-D and plasmin to produce several ntOPN species [32,52]. ntOPN derived from cleavage of OPNa isoform has been studied more extensively than ntOPN derived from OPNb and OPNc, which appears to mediate more pathobiological effects rather than homeostasis which may be a consequence of its enhanced affinity with integrin receptors [20,33,53] as its RGD motif is sterically more accessible. For example, it has been shown by Boggio et al. [54] that OPNa-derived ntOPN plays a significant role in multiple sclerosis by boosting the production of interleukin (IL)-17 and IL-6. ...
Osteopontin (OPN) is a ubiquitously expressed protein with a wide range of physiological functions, including roles in bone mineralization, immune regulation, and wound healing. OPN has been implicated in the pathogenesis of several forms of chronic kidney disease (CKD) where it promotes inflammation and fibrosis and regulates calcium and phosphate metabolism. OPN expression is increased in the kidneys, blood, and urine of patients with CKD, particularly in those with diabetic kidney disease and glomerulonephritis. The full-length OPN protein is cleaved by various proteases, including thrombin, matrix metalloproteinase (MMP)-3, MMP-7, cathepsin-D, and plasmin, producing N-terminal OPN (ntOPN), which may have more detrimental effects in CKD. Studies suggest that OPN may serve as a biomarker in CKD, and while more research is needed to fully evaluate and validate OPN and ntOPN as CKD biomarkers, the available evidence suggests that they are promising candidates for further investigation. Targeting OPN may be a potential treatment strategy. Several studies show that inhibition of OPN expression or activity can attenuate kidney injury and improve kidney function. In addition to its effects on kidney function, OPN has been linked to cardiovascular disease, which is a major cause of morbidity and mortality in patients with CKD.
... OPN is expressed in a variety of extracellular matrices (ECM) and regulates ECM remodeling (25). OPN is involved in a variety of pathophysiological processes, including bone metabolism, immune cell activation, cell migration, adhesion, and inhibition of apoptosis (26,27). These regulatory effects of OPN are mainly derived from three receptor domains. ...
... These regulatory effects of OPN are mainly derived from three receptor domains. The RGD domain binds to avb 1, 3, 5, 6, 8 , a 5, 8 b 1 , and a IIb b 3 integrins (26,28). SVVYGLR and nonconserved ELVTDFPTDLPAT domains engage a 9 b 1 , a 4 b 7 and a 4 b 1 integrins (29,30). ...
Osteopontin (OPN) is a multifunctional noncollagenous matrix phosphoprotein that is expressed both intracellularly and extracellularly in various tissues. As a growth regulatory protein and proinflammatory immunochemokine, OPN is involved in the pathological processes of many diseases. Recent studies have found that OPN is widely involved in the aging processes of multiple organs and tissues, such as T-cell senescence, atherosclerosis, skeletal muscle regeneration, osteoporosis, neurodegenerative changes, hematopoietic stem cell reconstruction, and retinal aging. However, the regulatory roles and mechanisms of OPN in the aging process of different tissues are not uniform, and OPN even has diverse roles in different developmental stages of the same tissue, generating uncertainty for the future study and utilization of OPN. In this review, we will summarize the regulatory role and molecular mechanism of OPN in different tissues and cells, such as the musculoskeletal system, central nervous system, cardiovascular system, liver, and eye, during senescence. We believe that a better understanding of the mechanism of OPN in the aging process will help us develop targeted and comprehensive therapeutic strategies to fight the spread of age-related diseases.
... Both human and mouse OPN contains the classical RGD motif that binds α v β 1 , α v β 3, α v β 5 , α v β 6 , α 5 β 1, and α 8 β 1 integrins (38)(39)(40). An additional integrin-binding motif is SVVYGLR 168 for hOPN or SLAYGLR 153 for mOPN. ...
... An additional integrin-binding motif is SVVYGLR 168 for hOPN or SLAYGLR 153 for mOPN. The 7-aa motifs are located immediately downstream of RGD and are called OPN "cryptic epitopes" due to their exposure upon thrombin cleavage between R 168 and S 169 residues in hOPN and between R 153 and S 154 in mOPN (39,41). In addition to thrombin, OPN is also cleaved by matrix metalloproteinase-3 (MMP-3) and MMP-7 between the G 166 and L 167 residues in hOPN and between G 151 and L 152 in mOPN (42)(43)(44)(45)(46)(47), which are within the SVVYGLR and SLAYGLR cryptic epitopes. ...
Link to the article
<<https://doi.org/10.1093/intimm/dxac060>>
Osteopontin (OPN) is a multifunctional protein, initially identified in osteosarcoma cells with its role of mediating osteoblast adhesion. Later studies revealed that OPN is associated with many inflammatory conditions caused by infections, allergic responses, autoimmunity, and tissue damage. Many cell types in the peripheral immune system express OPN with various functions, which could be beneficial or detrimental. Also, more recent studies demonstrated that OPN is highly expressed in the central nervous system (CNS), particularly in microglia during CNS diseases and development. However, understanding of mechanisms underlying OPN’s functions in the CNS is still limited. In this review, we focus on peripheral myeloid cells and CNS-resident cells to discuss the expression and functions of OPN.
... Promotes invasiveness [41] Basal Cell Promotes invasiveness [42] Liver Poor prognosis [43] Colon Cancer Involved in cell adhesion and migration, activation of TGF-B, regulation of extracellular proteases, poor prognosis marker and implications in cancer metastasis to liver [43][44][45][46][47][48] Gastric Prognostic marker [49] Cervical Squamous Unfavourable marker [50] Oral SCC Increased expression in invasive stage of the cancer, regulation of migration and adhesion of cancer cells [51][52][53] Pancreatic Enhanced expression, regulation of tumour angiogenesis [54,55] ...
Integrins are necessary for cell adhesion, migration, and positioning. Essential for inducing signalling events for cell survival, proliferation, and differentiation, they also trigger a variety of signal transduction pathways involved in mediating invasion, metastasis, and squamous-cell carcinoma. Several recent studies have demonstrated that the up- and down-regulation of the expression of αv and other integrins can be a potent marker of malignant diseases and patient prognosis. This review focuses on an arginine-glycine-aspartic acid (RGD)-dependent integrin αVβ6, its biology, and its role in healthy humans. We examine the implications of αVβ6 in cancer progression and the promotion of epithelial-mesenchymal transition (EMT) by contributing to the activation of transforming growth factor beta TGF-β. Although αvβ6 is crucial for proper function in healthy people, it has also been validated as a target for cancer treatment. This review briefly considers aspects of targeting αVβ6 in the clinic via different therapeutic modalities.
... These multifunctional biological roles are probably associated with the capacity for OPN to interact with different molecules, including cell surface receptors such as integrin and cluster of differentiation (CD44), intracellular signaling molecules, calcium, and heparin (4). OPN possesses three critical integrin binding sequences: the well conserved RGD domain (arginine-glycine-aspartic acid) that facilitated the interaction of OPN with αv integrins (especially αvβ1, αvβ3, and αvβ5); the SVVYGLR (serine-valine-valine-tyrosine-glutamate-leucine-arginine) domain, which may bind to α4β1, α4β7, and α9β1 integrins; and the ELVTDFP sequence on the N-terminal, which can bind α4β1 (5). The OPN protein is a member of the SIBLING (small integrin-binding ligand N-linked glycoprotein) family, whose members interact with CD44 and integrins through the characteristic domain. ...
Osteopontin (OPN) is a multifunctional glycoprotein that physiologically interacts with different types of integrins. It is considered to be a possible prognostic biomarker in certain tumor types; however, various splicing isoforms exist, which have not been investigated in melanoma. We aimed to define the relative expression pattern of five OPN isoforms and clarify the prognostic significance of the splice variants in melanoma. We also aimed to investigate the expression pattern of eight integrins in the same tumors. Gene expression analyses revealed that the relative expression of OPNa, OPNb , and OPNc is significantly higher in metastatic tumors compared to primary lesions ( p < 0.01), whereas the expression of OPN4 and OPN5 was low in both. The more aggressive nodular melanomas had higher expression levels compared to the superficial spreading subtype ( p ≤ 0.05). The relative expression of the eight tested integrins was low, with only the expression of ITGB3 being detectable in nodular melanoma (Median log2 = 1.274). A positive correlation was found between Breslow thickness and the expression of OPNc variant, whereby thicker tumors (>4 mm) had significantly higher expression ( p ≤ 0.05). The Breslow thickness was negatively correlated with the expression of OPN4 , and similarly with ITGA2 . OPNc also exhibited significant positive correlation with the presence of metastasis. Our data show that high expression of OPNa , OPNb , and especially OPNc and low expression of OPN4 and ITGA2 are associated with an advanced stage of tumor progression and poor prognosis in melanoma.
... Thrombin cleavage of OPN reveals a cryptic binding site for α9β1 integrin (S 162 VVYGLR 168 ) and the RGD domain, allowing for the α9β1 integrin-and RGD-binding integrin-mediated cell adhesion to the N-terminal fragment of OPN [159,160]. In contrast, the cleavage of recombinant OPN by MMP-3 abolishes the binding of α5β1 and α9β1 but not αvβ5 and αvβ6 integrins [161]. Therefore, the proteolytic processing may modulate the OPN functions in tumor progression. ...
Despite significant advances in the understanding of cancer biology, cancer is still a leading cause of death worldwide. Expression of the tumor microenvironment component, osteopontin, in tumor tissues, plasma, and serum, has been shown to be associated with a poor prognosis and survival rate in various human cancers. Recent studies suggest that osteopontin drives tumor development and aggressiveness using various strategies. In this review, we first provide an overview of how osteopontin promotes tumor progression, such as tumor growth, invasion, angiogenesis, and immune modulation, as well as metastasis and chemoresistance. Next, we address how the functional activities of osteopontin are modulated by the interaction with integrins and CD44 receptors, but also by the post-translational modification, such as proteolytic processing by several proteases, phosphorylation, and glycosylation. Then, we review how osteopontin activates tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), and functions as an immunosuppressor by regulating immune surveillance and immune checkpoint in the tumor microenvironment. Finally, we discuss the potential applications of osteopontin as a biomarker and as a therapeutic target.
... With the ELVTDFPTDL-PAT motif (in humans), osteopontin binds α4β1 integrin [51]. Thrombin cleavage is not required for the full adhesion to αvβ3-, αvβ5-, or αvβ6-integrins because they bind to the RGD domain of full osteopontin [44]. Via the C-terminal fragment calcium-binding site osteopontin interacts with the CD44 splice variants, CD44v3, CD44v6, and CD44v7 [52,53]. ...
... The majority of the effects of osteopontin are based on its ability to engage with various integrins and CD44 with its specific receptor binding domains ( Figure 1) [35]. The thrombin-cleaved N-terminal fragment of osteopontin binds to several integrins, including α4β1-, α4β7-, α5β1-, α9β1-, αvβ1-, αvβ3-αvβ5-, αvβ6-, and α5β1 via its two closely located but distinct motifs RGD and SVVYGLR (in mice, SLAYGLR) within the sequence 158 GRGDSVVYGLR 168 of receptor binding domains [33,[42][43][44][45][46][47][48]. Specifically, osteopontin interacts with αvβ1, αvβ3, and αvβ5 integrin receptors via the classical RGD sequence, while it interacts with α9β1, α4β1, α4β7 via SVVYGLR [42,49,50]. ...
... With the ELVTDFPTDLPAT motif (in humans), osteopontin binds α4β1 integrin [51]. Thrombin cleavage is not required for the full adhesion to αvβ3-, αvβ5-, or αvβ6-integrins because they bind to the RGD domain of full osteopontin [44]. Via the C-terminal fragment calcium-binding site osteopontin interacts with the CD44 splice variants, CD44v3, CD44v6, and CD44v7 [52,53]. ...
The matricellular protein osteopontin modulates cell–matrix interactions during tissue injury and healing. A complex multidomain structure of osteopontin enables it not only to bind diverse cell receptors but also to interact with various partners, including other extracellular matrix proteins, cytokines, and growth factors. Numerous studies have implicated osteopontin in the development and progression of myocardial remodeling in diverse cardiac diseases. Osteopontin influences myocardial remodeling by regulating extracellular matrix production, the activity of matrix metalloproteinases and various growth factors, inflammatory cell recruitment, myofibroblast differentiation, cardiomyocyte apoptosis, and myocardial vascularization. The exploitation of osteopontin loss- and gain-of-function approaches in rodent models provided an opportunity for assessment of the cell- and disease-specific contribution of osteopontin to myocardial remodeling. In this review, we summarize the recent knowledge on osteopontin regulation and its impact on various cardiac diseases, as well as delineate complex disease- and cell-specific roles of osteopontin in cardiac pathologies. We also discuss the current progress of therapeutics targeting osteopontin that may facilitate the development of a novel strategy for heart failure treatment.
