Analysis of the tetraspanin CD9–integrin <i>α</i>IIb<i>β</i>3 (GPIIb-IIIa) complex in platelet membranes and transfected cells

Indig, Fred E.; Dı́az-González, Federico; Ginsberg, Mark H.

doi:10.1042/bj3270291

Cited by 71 publications

(64 citation statements)

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“…311, Etablissement de Transfusion Sanguine de Strasbourg, Strasbourg, France), an integral membrane protein abundantly present in platelet membranes. 17 The A␤ antibody specifically stained ␤-amyloid deposits in brain tissue from patients with Alzheimer's disease, confirming its specificity. Double-labeling immunohistochemistry was performed to detect colocalization of iNOS or COX-2 with APP, A␤, or CD9.…”

Section: Immunohistochemical Study Of Advanced Human Atherosclerotic mentioning

confidence: 74%

Platelet Phagocytosis and Processing of β-Amyloid Precursor Protein as a Mechanism of Macrophage Activation in Atherosclerosis

Meyer

Cleen

Cooper

et al. 2002

Circulation Research

134

102

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Abstract-In human occluded saphenous vein grafts, we previously demonstrated cytotoxic foam cells, presumably derived from macrophages engulfing platelets. In the present study, we investigated whether platelet phagocytosis occurs in human atherosclerotic plaques, whether this activates macrophages, and whether the platelet constituent, amyloid precursor protein (APP), was involved. Immunohistochemistry documented the presence of APP, ␤-amyloid peptide (A␤, cleaved from APP), and platelets (CD9), along with inducible NO synthase (iNOS) and cyclooxygenase-2, two markers of macrophage activation, around microvessels in advanced human carotid artery plaques (nϭ18). A␤ colocalized with iNOS-expressing macrophages that were often surrounded by platelets. In vitro, murine J774 and human THP-1 macrophages were incubated with or without washed human platelets. Coincubation of macrophages and platelets led to platelet phagocytosis (electron and confocal microscopy) and formation of lipid-, APP-, and A␤-containing foam cells. These expressed iNOS mRNA (reverse transcription-polymerase chain reaction) and protein and produced nitrite and tumor necrosis factor-␣ (ELISA). Macrophage pretreatment with 4-(2-aminoethyl)benzenesulfonyl fluoride, a protease inhibitor, reduced APP processing and inhibited NO biosynthesis induced by platelet phagocytosis but not by lipopolysaccharides. Human atherosclerotic plaques and J774 and THP-1 macrophages contained mRNA of the APP-cleaving enzyme ␤-secretase. This is the first demonstration of A␤, a peptide extensively studied in Alzheimer's disease, in human atherosclerotic plaques. It was present in activated iNOSexpressing perivascular macrophages that had phagocytized platelets. In vitro studies indicate that platelet phagocytosis leads to macrophage activation and suggest that platelet-derived APP is proteolytically processed to A␤, resulting in iNOS induction. This represents a novel mechanism for macrophage activation in atherosclerosis. T he composition of an atherosclerotic plaque is an important determinant of plaque stability. Unstable ruptureprone plaques are characterized by a thin fibrous cap that contains few smooth muscle cells. 1,2 Several lines of evidence suggest that macrophage activation in the vulnerable shoulder of the plaque could contribute to plaque rupture. 3,4 We have previously postulated the release of factors toxic to smooth muscle cells, possibly NO, from activated macrophages in human atherosclerotic plaques. 5,6 It has been reported that foam cell formation can be induced by platelet phagocytosis. 7-10 Moreover, in human (sub)occluded saphenous vein grafts, the formation of toxic foam cells within mural thrombi is presumably the result of platelet phagocytosis by macrophages. 11 Therefore, we questioned whether in human atherosclerotic plaques platelet phagocytosis evokes macrophage activation and whether proteolytic processing of amyloid precursor protein (APP), present in platelet ␣-granules, 12-15 is involved in this process.To test this hypothesis, we fi...

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Section: Immunohistochemical Study Of Advanced Human Atherosclerotic mentioning

confidence: 74%

Platelet Phagocytosis and Processing of β-Amyloid Precursor Protein as a Mechanism of Macrophage Activation in Atherosclerosis

Meyer

Cleen

Cooper

et al. 2002

Circulation Research

134

102

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“…The ␣IIb␤3 integrin has been reported to be associated with CD9 and other membrane proteins. 32,33 We performed immunoprecipitations with the anti-CD36 antibody on platelets from a patient with Glanzmann thrombasthenia to establish that CD36 associates with the other proteins in the absence of ␣IIb␤3. The platelets from this patient contain about 3% of the normal levels of ␣IIb␤3 and contain normal levels of ␣v␤3.…”

Section: Resultsmentioning

confidence: 99%

“…Platelet CD36 has been reported to associate with ␣IIb␤3 that has, in turn, been reported to associate with CD9. 20,32,33 Dorahy et al 20 showed that CD36 and ␣IIb␤3 could be cross-linked to each other without evidence of inclusion of CD9. Rhinehart-Jones and Greenwalt 25 identified a 113 000-d species that reacts with antibodies to CD36 after platelets are cross-linked with bis (sulfosuccinimidyl) suberate.…”

Section: Discussionmentioning

confidence: 99%

CD36 associates with CD9 and integrins on human blood platelets

Miao

Vasile

Lane

et al. 2001

Blood

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The membrane glycoprotein CD36 is involved in platelet aggregation, inhibition of angiogenesis, atherosclerosis, and sequestration of malaria-parasitized erythrocytes. In this study, immunoprecipitations with anti-CD36 antibodies were performed to identify proteins that associate with CD36 in the platelet membrane. Platelets were solubilized in 1% Triton X-100, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), Brij 96, or Brij 99, and the proteins that coprecipitated with CD36 were identified by peptide mass spectrometry and Western blotting. The tetraspanin protein CD9 and the integrins ␣IIb␤3 and ␣6␤1 specifically coprecipitated with CD36 from platelets that were solubilized in CHAPS and Brij 99 but not from platelets that were solubilized in Triton X-100. Only CD9 is coprecipitated with CD36 from platelets that were solubilized in Brij 96. Reciprocal immunoprecipitations with antibodies to CD9, ␣6, ␣IIb, or ␤3 from Brij 99-solubilized platelets coprecipitated CD36. Coprecipitation of CD36, CD9, and ␣6␤1 was also observed on platelets from a patient with Glanzmann thrombasthenia, indicating that ␣IIb␤3 is not required for the other proteins to associate. Colocalization of ␣6 and CD36, of CD9 and CD36, and of ␣6 and CD9 was observed on intact platelets prior to solubilization, using double immunofluorescence microscopy. These data indicate that CD36 associates with CD9 and integrins on human blood platelets. These associated proteins may mediate or participate in some of the diverse biological functions of CD36. ( IntroductionCD36 is a transmembrane glycoprotein that has been shown to participate in multiple biological functions, including platelet aggregation, inhibition of angiogenesis, uptake of oxidized lowdensity lipoprotein and long-chain fatty acids, cell adhesion, and the sequestration of Plasmodium falciparum-infected erythrocytes. 1 As a scavenger receptor, CD36 is involved in the uptake of oxidized low-density lipoprotein by macrophages and the formation of foam cells during arterial atherogenesis. [2][3][4] As a thrombospondin 1 (TSP-1) receptor on platelets, CD36 is involved in reinforcing the molecular bridge that is formed between platelets by fibrinogen and the ␣IIb␤3 integrin during aggregation. [5][6][7] This model is supported by observations that antibodies to TSP-1 inhibit platelet aggregation (for review see Lawler 8 ). As a TSP-1 receptor on endothelial cells, CD36 reportedly mediates the antiangiogenic effect of TSP-1. 9 The effect of TSP-1 on angiogenesis involves the inhibition of endothelial cell migration and the induction of apoptosis. The latter effect reportedly involves the activation of p38 mitogen-activated protein kinase and caspases. 9 The original fluid mosaic model of the plasma membrane visualized membrane proteins as free-floating entities in a sea of lipids. 10 Data indicate that the plasma membrane is far less homogeneous than this model implies. [10][11][12][13][14] Membrane proteins and lipids associate to form functional domains in the plasma membra...

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“…They form protein complexes that are mostly composed of different tetraspanins and integrins, but can also contain members of other protein families Horvath et al, 1998;Indig et al, 1997;Lozahic et al, 2000;Mannion et al, 1996;Rubinstein et al, 1997;Scherberich et al, 1998;Serru et al, 1999;Sincock et al, 1999;Tiwari-Woodruff et al, 2001;Yauch et al, 1998). The strongest association between tetraspanins and integrins has been described for CD151 and the α3 and α6 integrins Yauch et al, 1998;Yauch et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

The association of the tetraspanin D6.1A with the α6β4 integrin supports cell motility and liver metastasis formation

Herlevsen

Schmidt

Miyazaki

et al. 2003

Journal of Cell Science

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The metastatic subline of a rat pancreatic adenocarcinoma differs from the non-metastasizing subline by overexpression of 5 membrane molecules: CD44 variant isoforms, EpCAM, the tetraspanin D6.1A, an uPAR-related molecule and, as described here, the α6β4 integrin.An antibody-defined molecule was identified by mass spectrometry and cloning as α6β4 integrin. Transfectioninduced expression of α6β4 in the non-metastasizing subline did not support migration on laminin 5 or tumor progression. However, when the non-metastasizing subline was doubly transfected to express α6β4 and the D6.1A tetraspanin, intraperitoneally injected tumor cells frequently formed liver metastasis. For the following reasons we assume that metastasis formation is supported by an interaction between α6β4 and D6.1A. (i) The 2 molecules can associate and co-localize. (ii) Co-localization is strengthened by PKC stimulation. (iii) PKC stimulation, which induces a migratory phenotype, leads to a redistribution of α6β4/D6.1A complexes. In resting cells, the molecules co-localize at the trail of the cell; during PKC stimulation they become transiently internalized and are (re-)expressed in the leading lamella. Thus, in the appropriate milieu, i.e. intraperitoneally, α6β4 changes from an adhesion-supporting towards a migrationsupporting molecule by its association with a tetraspanin. The findings provide a convincing experimental explanation for the repeatedly described involvement of α6β4 in tumor progression.Key words: α6β4 integrin, Tetraspanin, Metastasis, Adhesion, Motility SummaryThe association of the tetraspanin D6.1A with the α6β4 integrin supports cell motility and liver metastasis formation

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Analysis of the tetraspanin CD9–integrin αIIbβ3 (GPIIb-IIIa) complex in platelet membranes and transfected cells

Cited by 71 publications

References 50 publications

Platelet Phagocytosis and Processing of β-Amyloid Precursor Protein as a Mechanism of Macrophage Activation in Atherosclerosis

Platelet Phagocytosis and Processing of β-Amyloid Precursor Protein as a Mechanism of Macrophage Activation in Atherosclerosis

CD36 associates with CD9 and integrins on human blood platelets

The association of the tetraspanin D6.1A with the α6β4 integrin supports cell motility and liver metastasis formation

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