Engagement of alpha IIb beta 3 (GPIIb/IIIa) with alpha nu beta 3 Integrin Mediates Interaction of Melanoma Cells with Platelets A CONNECTION TO HEMATOGENOUS METASTASIS
Anke S. LonsdorfBjoern F. KraemerManuela FahrleitnerTanja SchoenbergerStephan GnerlichSabine RingSarah GehringStefan W. SchneiderMichael J. KruhlakSven G. MeuthBernhard NieswandtMeinrad GawazAlexander EnkHarald F. Langer
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Abstract Recent in situ studies suggest the α v β 3 integrin is a tumour progression marker in melanoma. We analyzed 5 human melanoma cell lines for their expression of the vitronectin binding α v β 3 and α v β 5 , integrins using flow cytometry. The role of these receptors in cell attachment, spreading and migration was investigated using attachment assays, video time lapse spreading and migration assays and with function blocking monoclonal antibodies. Cell lines derived from later stages of tumor progression exhibited high levels of α v β 3 expression, whereas no similar correlation with α v β 5 expression was identified. Cell attachment, spreading and migration response on vitronectin correlated well with the expression level of the α v β 3 but not the α v β 5 vitronectin receptor. Blocking of the α v β 3 integrin resulted in a significant decrease in cell attachment, spreading and motility whereas the function blocking antibody against the α v β 5 integrin only inhibited cell attachment in cell lines with the highest level of expression of this integrin. Taken together, our study indicates that the level of expression of the α v β 3 and α v β 5 integrins is heterogeneous in melanoma cell lines and that the α v β 5 integrin, if present, may function only during the initial cell attachment whereas the α v β 3 plays an important rôle in cell spreading and cell migration as well.
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The integrins GPIIb-IIIa and alpha beta and the integrin subunits alpha , alpha and beta have been shown by flow cytometry v 3 to be present on the surface of CHRF 288-11 megakaryoblastic cells grown in culture. PMA-induced differentiation of these cells caused a rapid increase in the surface expression of alpha beta , the vitronectin receptor, and a delayed decrease in surface expression of the alpha subunit (presumably present as the alpha beta integrin of the 5 fibronectin receptor). PMA caused no change in expression of GPIIb-IIIa, the alpha subunit (presumably present as alpha beta ) or of the beta subunit overall. GPIIb-IIIa appeared to be present as an inactive complex on these 2 1 1 cells. 2 5 1 v 3 5 1 2
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Glycoprotein IIb-IIIa (alpha IIb beta 3) and the vitronectin receptor (alpha v beta 3), two integrins that share the common beta 3 subunit, have been reported to function as promiscuous receptors for the RGD-containing adhesive proteins fibrinogen, vitronectin, fibronectin, von Willebrand factor, and thrombospondin. The present study was designed to establish a cell system for the expression of either GP IIb-IIIa or the vitronectin receptor in an otherwise identical cellular environment and to compare the adhesive properties of these two integrins with those of native GP IIb-IIIa and the vitronectin receptor constitutively expressed in HEL cells or platelets. M21 human melanoma cells lack GP IIb-IIIa and use the vitronectin receptor to attach to vitronectin, fibrinogen, fibronectin, and von Willebrand factor. To study the functional properties of GP IIb-IIIa in these cells, we transfected GP IIb into M21-L cells, a variant of M21 cells (Cheresh, D.A., and R.C. Spiro. 1987. J. Biol. Chem. 262:17703-17711), which lack the expression of functional alpha v and are therefore unable to attach to vitronectin, fibrinogen, and von Willebrand factor. Transfectants expressing GP IIb were isolated by immunomagnetic beads and surface expression of the GP IIb-IIIa complex was documented by FACS analysis and immunoprecipitation experiments performed with 125I-labeled M21-L/GP IIb cells. Comparative functional studies demonstrated that GP IIb-IIIa expressed in M21-L/GPIIb cells as well as native GP IIb-IIIa constitutively expressed in HEL-5J20 cells (an HEL variant lacking alpha v beta 3) mediated cell attachment to immobilized fibrinogen, but not to vitronectin or von Willebrand factor, whereas the vitronectin receptor expressed in M21 cells and HEL-AD1 cells (an HEL variant expressing alpha v beta 3) mediated cell attachment to fibrinogen, vitronectin, and von Willebrand factor. Similarly, PGl2-treated resting platelets attached to immobilized fibrinogen but not to vitronectin or von Willebrand factor, and this attachment could be inhibited by mAb A2A9 (directed against a functional site on the GP IIb-IIIa complex). However, in contrast to platelets, which adhered to vitronectin and von Willebrand factor after stimulation by thrombin or PMA, activation of the protein kinase C pathway in M21-L/GP IIb or HEL cells did not induce cell adhesion to vitronectin or von Willebrand factor.(ABSTRACT TRUNCATED AT 400 WORDS)
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