Differential expression of immunomodulatory galectin-1 in peripheral leukocytes and adult tissues and its cytosolic organization in striated muscle

Dias‐Baruffi, Marcelo; Stowell, Sean R.; Song, Shuh-Chyung; Arthur, Connie M.; Cho, Moonjae; Rodrigues, Lílian Cataldi; Montes, Marlise A. B.; Rossi, Marcos A.; James, Judith A.; McEver, Rodger P.; Cummings, Richard D.

doi:10.1093/glycob/cwp203

Cited by 47 publications

(47 citation statements)

References 67 publications

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“…Interestingly, in human adult tissue, highly related SPRED2 can be found in the liver and small intestine (71), where Gal-1 is also expressed (79). It is thus possible that the observations that we have made here also apply to the functioning of SPRED2.…”

Section: Discussionmentioning

confidence: 63%

SPRED1 Interferes with K-ras but Not H-ras Membrane Anchorage and Signaling

Siljamäki

Abankwa

2016

Molecular and Cellular Biology

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The Ras/mitogen-activated protein kinase (MAPK) signaling pathway is tightly controlled by negative feedback regulators, such as the tumor suppressor SPRED1. The SPRED1 gene also carries loss-of-function mutations in the RASopathy Legius syndrome. Growth factor stimulation translocates SPRED1 to the plasma membrane, triggering its inhibitory activity. However, it remains unclear whether SPRED1 there acts at the level of Ras or Raf. We show that pharmacological or galectin-1 (Gal-1)-mediated induction of B-and C-Raf-containing dimers translocates SPRED1 to the plasma membrane. This is facilitated in particular by SPRED1 interaction with B-Raf and, via its N terminus, with Gal-1. The physiological significance of these novel interactions is supported by two Legius syndrome-associated mutations that show diminished binding to both Gal-1 and B-Raf. On the plasma membrane, SPRED1 becomes enriched in acidic membrane domains to specifically perturb membrane organization and extracellular signal-regulated kinase (ERK) signaling of active K-ras4B (here, K-ras) but not H-ras. However, SPRED1 also blocks on the nanoscale the positive effects of Gal-1 on H-ras. Therefore, a combinatorial expression of SPRED1 and Gal-1 potentially regulates specific patterns of K-ras-and H-ras-dependent signaling output. More broadly, our results open up the possibility that related SPRED and Sprouty proteins act in a similar Ras and Raf isoform-specific manner.S PRED (Sprouty-related proteins with an EVH1 domain) proteins are Sprouty-related negative modulators of Ras/mitogen-activated protein kinase (MAPK) signaling, and they have been shown to attenuate extracellular signal-regulated kinase (ERK) activity following various extracellular mitogenic stimuli (e.g., growth factors, cytokines, and chemokines) (1-5). The mammalian SPRED family contains four members, SPRED1, SPRED2, SPRED3, and Eve-3, the last of which is a splice variant of SPRED3 (1, 2, 6). SPRED1 and SPRED2 proteins contain an N-terminal enabled/vasodilator-stimulated phosphoprotein homology-1 (EVH1) domain and a cysteine-rich C-terminal Sprouty-related (SPR) domain, separated by a small c-Kit-binding domain (KBD) (2, 7). The SPR domain is necessary for membrane anchoring following growth factor stimulation (5), and both EVH1 and SPR domains have been implicated in ERK suppression (5,8,9). SPRED3 lacks a functional KBD and shows lower inhibitory activity than SPRED1 and -2, suggesting that the KBD also participates in inhibiting ERK activity (1-5).The precise mechanism of action of how SPRED proteins block MAPK signaling remains unclear. Overexpression of SPRED1 was suggested to increase the recruitment of the Ras effector Raf to the plasma membrane, where its association with Ras does not, however, lead to Raf activation (1, 2, 6). Instead, SPRED1 was reported to prolong Ras-Raf complexation, thus withdrawing Raf from activation by phosphorylation (2, 7). Another study showed that overexpression of SPRED1 inhibits Ras activation, as evidenced by decreased levels of GTP-bound ...

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Section: Discussionmentioning

confidence: 63%

SPRED1 Interferes with K-ras but Not H-ras Membrane Anchorage and Signaling

Siljamäki

Abankwa

2016

Molecular and Cellular Biology

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“…These galectins are expressed in many different cell types (including endothelial cells, platelets, and macrophages) and are also present in normal plasma. 26,27,[34][35][36] In this study, we demonstrate for the first time that FVIII can interact with at least 2 members of the galectin family (Gal-1 and Gal-3, respectively). Although a large number of putative galectin-binding partners have previously been described, our data demonstrate that the apparent affinities of Gal-1 and Gal-3 for pd-FVIII (in the range 0.12-0.47 nmol/L) are unusually high compared with those reported for other galectin-glycoprotein interactions.…”

Section: Discussionmentioning

confidence: 65%

“…48 Furthermore, Gal-1 is also expressed within EC, where it is stored together with VWF within Weibel Palade bodies and secreted after EC activation. 26,28,34 In addition, markedly elevated systemic plasma galectin levels have also been demonstrated in association with many pathological conditions, including acute inflammatory disorders and metastatic malignancy. 27,50,51 Interestingly, a series of elegant recent studies have identified novel roles for Gal-1, Gal-3, and Gal-3-binding protein in the pathogenesis of venous thrombosis.…”

Section: Downloaded Frommentioning

confidence: 99%

Galectin-1 and Galectin-3 Constitute Novel-Binding Partners for Factor VIII

O’Sullivan

Jenkins

Rawley

et al. 2016

ATVB

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Objective-Recent studies have demonstrated that galectin-1 (Gal-1) and galectin-3 (Gal-3) can bind von Willebrand factor and directly modulate von Willebrand factor-dependent early thrombus formation in vivo. Because the glycans expressed on human factor VIII (FVIII) are similar to those of von Willebrand factor, we investigated whether galectins might also bind and modulate the activity of FVIII. Approach and Results-Immunosorbant assays and surface plasmon resonance analysis confirmed that Gal-1 and Gal-3 bound purified FVIII with high affinity. Exoglycosidase removal of FVIII N-linked glycans significantly reduced binding to both Gal-1 and Gal-3. Moreover, combined removal of both the N-and O-glycans of FVIII further attenuated Gal-3 binding. Notably, specific digestion of FVIII high-mannose glycans at N239 and N2118 significantly impaired FVIII affinity for Gal-1. Importantly Gal-1, but not Gal-3, bound to free FVIII in the plasma milieu, and significantly inhibited FVIII functional activity. Interestingly, commercial recombinant FVIII (rFVIII) concentrates are manufactured in different cell lines and differ in their glycosylation profiles. Although the biological mechanism has not been defined, recent studies in previously untreated patients with severe hemophilia A reported significant differences in inhibitor development associated with different rFVIII products. Interestingly, Gal-1 and Gal-3 both displayed enhanced affinity for BHK-rFVIII compared with CHO-rFVIII. Furthermore, binding of Gal-1 and Gal-3 to BDD-FVIII was markedly reduced compared with full-length rFVIII. Conclusions-We have identified Gal-1 and Gal-3 as novel-binding partners for human FVIII and demonstrated that Gal-1 binding can influence the procoagulant activity of FVIII.

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“…[24][25][26] This led us to hypothesize that perhaps part of the Gal-1 and Gal-3 proteins could colocalize with VWF, the majority of which is located in endothelial storage organelles, the WP bodies. To test for colocalization, we applied Duolink-PLA analysis, which detects proteins located within a radius of Ͻ40 nm.…”

Section: Gal-1 and Gal-3 Are Associated With Vwf In Endothelial Cellsmentioning

confidence: 99%

“…24 In particular, galectin-1 (Gal-1) and galectin-3 (Gal-3) are being abundantly expressed in the endothelium. [24][25][26] Moreover, glycan array analysis has revealed that both Gal-1 and Gal-3 are able to recognize carbohydrate structures that are present on the VWF molecule. 27 Here, we explored the possibility that Gal-1 and Gal-3 are able to interact with VWF.…”

mentioning

confidence: 99%

Identification of Galectin-1 and Galectin-3 as Novel Partners for Von Willebrand Factor

Saint-Lu

Oortwijn

Pegon

et al. 2012

ATVB

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Objective-Although von Willebrand factor (VWF) is a heavily glycosylated protein, its potential to associate with glycan-binding proteins is poorly investigated. Here, we explored its interaction with the glycan-binding proteins galectin-1 and galectin-3. Methods and Results-Immunofluorescence analysis using Duolink proximity ligation assays revealed that VWF colocalizes with galectin-1 and galectin-3 in endothelial cells, both before and after stimulation of endothelial cells. Moreover, galectin-1 was found along the typical VWF bundles that are released by endothelial cells. Galectin-1 and galectin-3 could be coprecipitated with VWF from plasma in immunoprecipitation assays, whereas plasma levels of galectin-1 and galectin-3 were significantly reduced in VWF-deficient mice. Binding studies using purified proteins confirmed that VWF could directly interact with both galectins, predominantly via its N-linked glycans. In search of the physiological relevance of the VWF-galectin interaction, we found that inhibition of galectins in in vitro perfusion assays was associated with increased VWF-platelet string formation, a phenomenon that was reproduced in galectin-1/galectin-3 double-deficient mice. These mice were also characterized by a more rapid formation of initial thrombi following ferric chloride-induced injury. Key Words: endothelium Ⅲ hemostasis Ⅲ platelets Ⅲ galectin Ⅲ von Willebrand factor V on Willebrand factor (VWF) is an adhesive protein that is critical to the recruitment of platelets in response to vessel injury. The majority of the circulating VWF molecules are produced in the endothelial cells, where VWF is synthesized as a single prepropolypeptide chain. Following signal peptide removal, the polypeptides are assembled into C-terminal linked pro-VWF dimers. Further processing includes proteolytic removal of the propeptide and multimerization of the molecule by intermolecular N-terminal cystine bonding, generating a pool of differentially sized multimers that may contain more than 50 subunits. An important portion of the newly synthesized VWF multimers is directed to endothelial storage organelles, Weibel-Palade (WP) bodies. Conclusion-We1,2 VWF is obligatory for the formation of WP bodies, which are indeed absent in endothelial cells isolated from VWF-deficient mice or dogs.3,4 These storage organelles also contain other proteins besides VWF, including P-selectin, osteoprotegerin, CD63, and interleukin-8. 5 Some of these proteins directly interact with VWF, which may facilitate their uptake into the WP bodies. 6,7 For other residents of the storage granules, the uptake may be the result of a more random inclusion process. 8 Following endothelial stimulation, the content of the WP bodies is released into the circulation, allowing the first encounter between VWF and circulating platelets. Indeed, VWF multimers assemble into twisted bundles and networks that form long strings along the endothelial surface. 9 These VWF strings are able to catch platelets, and these platelet-decorated strings can be vis...

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Differential expression of immunomodulatory galectin-1 in peripheral leukocytes and adult tissues and its cytosolic organization in striated muscle

Cited by 47 publications

References 67 publications

SPRED1 Interferes with K-ras but Not H-ras Membrane Anchorage and Signaling

SPRED1 Interferes with K-ras but Not H-ras Membrane Anchorage and Signaling

Galectin-1 and Galectin-3 Constitute Novel-Binding Partners for Factor VIII

Identification of Galectin-1 and Galectin-3 as Novel Partners for Von Willebrand Factor

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