Further characterization of the cellular plasminogen binding site: evidence that plasminogen 2 and lipoprotein a compete for the same site

Gonzalez-Gronow, Mario; Edelberg, Jay M.; Pizzo, Salvatore V.

doi:10.1021/bi00432a005

Cited by 223 publications

(83 citation statements)

References 39 publications

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“…There seem to be no obvious underlying principles that can predict which proteins will bind angiostatin and which will not. In this regard, angiostatins are no different than their parent molecule plasminogen, which itself binds to a plethora of cell surface, soluble, and matrix-associated targets [see Gonzalez-Gronow et al, 1989, 1998Stack et al, 1992aStack et al, ,b, 1994] and references therein). As a zymogen that is activated during fibrinolysis, plasminogen undergoes multiple binding events as a normal part of its biology.…”

Section: Discussionmentioning

confidence: 99%

Angiostatin's molecular mechanism: Aspects of specificity and regulation elucidated

Wahl

Kenan

Gonzalez-Gronow

et al. 2005

J of Cellular Biochemistry

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114

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Tumor growth requires the development of new vessels that sprout from pre-existing normal vessels in a process known as ''angiogenesis'' [Folkman (1971) N Engl J Med 285:1182-1186. These new vessels arise from local capillaries, arteries, and veins in response to the release of soluble growth factors from the tumor mass, enabling these tumors to grow beyond the diffusion-limited size of approximately 2 mm diameter. Angiostatin, a naturally occurring inhibitor of angiogenesis, was discovered based on its ability to block tumor growth in vivo by inhibiting the formation of new tumor blood vessels [O'Reilly et al. (1994a) Cold Spring Harb Symp Quant Biol 59:471-482]. Angiostatin is a proteolytically derived internal fragment of plasminogen and may contain various members of the five plasminogen ''kringle'' domains, depending on the exact sites of proteolysis. Different forms of angiostatin have measurably different activities, suggesting that much remains to be elucidated about angiostatin biology. A number of groups have sought to identify the native cell surface binding site(s) for angiostatin, resulting in at least five different binding sites proposed for angiostatin on the surface of endothelial cells (EC). This review will consider the data supporting all of the various reported angiostatin binding sites and will focus particular attention on the angiostatin binding protein identified by our group: F 1 F O ATP synthase. There have been several developments in the quest to elucidate the mechanism of action of angiostatin and the regulation of its receptor. The purpose of this review is to describe the highlights of research on the mechanism of action of angiostatin, its' interaction with ATP synthase on the EC surface, modulators of its activity, and issues that should be explored in future research related to angiostatin and other anti-angiogenic agents.

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Section: Discussionmentioning

confidence: 99%

Angiostatin's molecular mechanism: Aspects of specificity and regulation elucidated

Wahl

Kenan

Gonzalez-Gronow

et al. 2005

J of Cellular Biochemistry

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114

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“…10 The reported high homology of apo(a) to plasminogen"' 13 supports the hypothesis that Lp(a) might be the "missing link" between thrombogenesis and atherogenesis. able to compete with plasminogen for the same binding site on monocytoid U937 cells 14 and endothelial cells.…”

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confidence: 99%

Identification of glycoprotein IIb as the lipoprotein(a)-binding protein on platelets. Lipoprotein(a) binding is independent of an arginyl-glycyl-aspartate tripeptide located in apolipoprotein(a).

Malle

Ibovnik

Stienmetz

et al. 1994

Arterioscler Thromb

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Lipoprotein(a) [Lp(a)] plays an important role in atherosclerosis. The amino acid sequence of apolipoprotein(a) [apo(a)] reveals an arginyl-glycyl-aspartate (RGD) tripeptide that is the consensus sequence for binding of adhesive plasma proteins of the fibrinolytic system, such as fibrinogen and von Willebrand factor, to the platelet membrane glycoprotein Ilb-IIIa (GPIIb-IIIa) complex. Therefore, we undertook the present study to further investigate the role of Lp(a) in hemostasis. Binding of 12S I-Lp(a) to a single platelet membrane-associated protein (137±6 kD) comigrating with platelet GPIIb (140 kD) was found to be specific, saturable, and Ca 2+ independent. Binding of 125 I-Lp(a) to resting human blood platelets was saturable, insensitive to temperature, and independent of the apo(a) isoform (B, SI through S3). Scatchard analysis revealed a K d of 7.2± 1.8x10"' mol/L, with 729±313 Lp(a) molecules bound per platelet. Monoclonal anti-GPIIb IgG diminished Lp(a) binding by approximately 80%, monoclonal anti-GPIIb-IIIa IgG by 60%, and antiGPIIIa IgG by just 15%.l23 I-Lp(a) binding was competitively T he main physiological role of platelets in the hemostatic system is to provide the initial protection against hemorrhage after an interruption of vascular integrity. Thus, whenever the continuous interior layer of vascular endothelium is interrupted, platelets become attached to exposed subendothelium. The subsequent activation of platelets and their adhesion to the fibrin network are key elements in the formation of a thrombus' -a process that involves a variety of receptor-mediated steps. Conversion of platelet membrane glycoprotein lib (GPIIb) and GPIIIa from the latent state to the GPIIb-IIIa complex provides a specific binding site for adhesive plasma proteins of the fibrinolytic system such as fibrinogen, fibronectin, von WilleReceived September 23, 1993; revision accepted October 28, 1993.From the Department of Internal Medicine, Division of Endocrinology and Metabolism, Philipps University, Marburg, Germany (E.M., A.S.); the Institute of Medical Biochemistry, KarlFranzens University, Graz, Austria (E.M., A.I., G.M.K.); and the Heart Research Institute, Biochemistry Group, Sydney, Australia (W.S.).Presented in part at the Fourth Erfurt Conference on Platelets, June 1992, Erfurt, Germany, and published in abstract form {Platelets. 1993;4:105).Reprint requests to Dr Wolfgang Sattler, Karl-Franzens University, Institute of Medical Biochemistry, Harrachgasse 21, A-8010 Graz, Austria.inhibited to the same extent by either unlabeled Lp(a) or fibrinogen. Low-and high-density lipoproteins were much weaker competitors. A polyclonal antibody raised against the RGDGQSYRGT sequence of apo(a) was used to verify the presence of an RGD sequence in the different Lp(a) preparations investigated. However, two lines of evidence indicated that the RGD sequence is not the binding domain mediating Lp(a) binding to platelets. First, incubation of platelets with isolated RGD tripeptide did not influence Lp(a) binding. Second...

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“…In addition, neonatal Pg 2, which has 18 times more NeuNAc than adult Pg 2, is activated 6-fold less efficiently by tPA (10). Pg 2 also binds to cell surfaces with greater affinity than the more glycosylated Pg 1 (11). Unglycosylated Pg, expressed in Escherichia coli, was resistant to activation by tPA and uPA and was cleared significantly faster than glycosylated Pg molecules (5).…”

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confidence: 99%

Evidence for a Novel O-Linked Sialylated Trisaccharide on Ser-248 of Human Plasminogen 2

Pirie-Shepherd

Stevens

Andon

et al. 1997

Journal of Biological Chemistry

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Human plasminogen, the inactive precursor of plasmin, exists in two major glycoforms. Plasminogen 1 contains an N-linked oligosaccharide at Asn-289 and an Olinked oligosaccharide at Thr-345. Plasminogen 2 is known to contain only an O-linked oligosaccharide at Thr-345. However, plasminogen 2 displays a further well documented microheterogeneity dependent on the Nacetylneuraminic acid content, which has functional consequences with regard to activation of plasminogen. The proposed structure and number of known oligosaccharide linkages in plasminogen 2 is insufficient to account for this microheterogeneity. In the present study, a combination of trypsin digestion, lectin affinity chromatography, Edman degradation amino acid sequence analysis, carbohydrate composition analysis, and mass spectrometry revealed the existence of a novel site for O-linked glycosylation on plasminogen 2 at Ser-248. Direct evidence for the structure of the carbohydrate was obtained from a combination of lectin affinity chromatography, desialylation experiments, and mass spectrometry analysis. These findings provide a structural basis for some of the observed microheterogeneity, and have implications with regard to the known functional consequences of the extent of sialylation of plasminogen.

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Further characterization of the cellular plasminogen binding site: evidence that plasminogen 2 and lipoprotein a compete for the same site

Cited by 223 publications

References 39 publications

Angiostatin's molecular mechanism: Aspects of specificity and regulation elucidated

Angiostatin's molecular mechanism: Aspects of specificity and regulation elucidated

Identification of glycoprotein IIb as the lipoprotein(a)-binding protein on platelets. Lipoprotein(a) binding is independent of an arginyl-glycyl-aspartate tripeptide located in apolipoprotein(a).

Evidence for a Novel O-Linked Sialylated Trisaccharide on Ser-248 of Human Plasminogen 2

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