Copyright © 2006, European Society of Cardiology
SCUBE1 – A new scoop in vascular biology?
Medizinische Klinik III, Eberhard Karls Universität Tübingen, Otfried-Müller-Str. 10, D-72076 Tübingen, Germany
* Corresponding authors. Tel.: +49 7071 29 83688; fax: +49 7071 29 5749. Email address: stephan.lindemann{at}med.uni-tuebingen.de meinrad.gawaz{at}med.uni-tuebingen.de
Received 23 May 2006; accepted 2 June 2006
See article by Tu et al. [6] (pages 486–495) in this issue.
Platelets represent an important link between inflammation, thrombosis, and vascular and tissue repair mechanisms. Once activated, platelets generate and release an arsenal of potent inflammatory, proliferative, and mitogenic substances into the local microenvironment of vascular lesions [1]. Thereby, platelets control and effect multiple mechanisms of cellular function involved in vascular and tissue repair.
The epidermal growth factor (EGF) superfamily is a group of growth factors, cytokine-like mediators, and extracellular matrix proteins. A new gene of an EGF-related protein was isolated 6 years ago in developing mice [2]. This new mammalian gene encodes a protein with a signal peptide at the amino-terminus followed by several EGF-like repeats and one CUB-domain at the carboxyl terminus. This gene family was termed SCUBE for signal-peptide-CUB-EGF-like domain-containing proteins.
Shortly after the discovery of the SCUBE1 gene, a closely related gene, SCUBE2, was described [3]. Initially, both genes were believed to play a role in embryonic development, which may still be the case. However, the gene product was then identified in human vascular endothelial cells by the same group that now presents its work about SCUBE1 expressed in platelets and atherosclerotic vascular lesions.
In vascular endothelial cells, SCUBE1 and SCUBE2 are secreted glycoproteins that appear on the cell surface as stable oligomers. With endothelial activation, e.g. by interleukin-1β or TNF-
, the expression of both proteins is rapidly downregulated [4]. This was the first hint of a potential involvement of the SCUBE proteins in inflammation. Initially, in the human system, SCUBE1 was only detected in endothelial cells (ECs) while SCUBE2 was expressed in ECs as well as in many other cell types. A recently described third SCUBE protein, SCUBE3, was detected solely in bone tissue [5].
Now – and this is the most exciting discovery since the description of the SCUBE-gene product family – Tu et al. [6] report in the current issue of Cardiovascular Research that SCUBE1 is highly expressed in platelets. They show that SCUBE1 in platelets is localized in the -granules and transferred to the cell surface upon activation and aggregation. Furthermore, they detected SCUBE1 mRNA in human platelets, although they did not check whether platelets are able to generate new SCUBE1 protein from their own mRNA pool. A complete translational machinery in platelets was recently demonstrated, and platelets are able to translate mRNAs into protein, depending on conditions [7,8]. Our group has shown that platelets are able to translate the constitutive interleukin-1β mRNA into protein on a long-term basis when they aggregate [9]. So far, active SCUBE1 translation in platelets is just speculation, since the SCUBE mRNA can also be just an inactive relict from the mother cell, the megakaryocyte.
We have established a model that generates new platelets from endothelial progenitor cells [10]. These platelets have the same phenotype, surface protein expression, and aggregation and adhesion behaviour as native platelets from donors, but it is possible to silence single genes by si-RNAs. It will be a very exciting experiment to silence the gene for SCUBE1 and to observe the functional consequences.
Adhesion and aggregation experiments revealed that recombinant fragments of SCUBE enhanced platelet aggregation and adhesion. SCUBE1 was also detected in platelet-rich thrombi and in atherosclerotic lesions. Most likely, SCUBE1 is released by activated and adherent platelets and sticks to the sub-endothelial matrix. The function of SCUBE1 in the atherosclerotic plaque or thrombus is unclear. Also unclear is why SCUBE1 is released by activated platelets but is downregulated in activated endothelium. Both facts may implicate the involvement of SCUBE1 in pathophysiological conditions such as atherosclerosis or vascular repair. However, these contradictory expression patterns in activated endothelial cells and in activated platelets leave open the question whether SCUBE1 enhances or attenuates vascular or tissue repair mechanisms involved in diseases such as atherosclerosis or remodelling of ischemic myocardium. Evaluation of inhibition strategies that are directed against SCUBE1 in suitable animal models is required and will help to answer this question.
Like every good scientific story, the study by Tu et al. [6] generates more questions about the role of SCUBE1 in platelet and vascular biology than it answers. Let's set off for new horizons!
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[Abstract/Free Full Text] - Wu B.T., Su Y.H., Tsai M.T., Wasserman S.M., Topper J.N., Yang R.B. A novel secreted, cell-surface glycoprotein containing multiple epidermal growth factor-like repeats and one CUB domain is highly expressed in primary osteoblasts and bones. J Biol Chem (2004) 279:37485–37490.
[Abstract/Free Full Text] - Tu C.F., Su Y.H., Huang Y., Tsai M.T., Li L.T., Chen Y.L., et al. Localization and characterization of a novel secreted protein SCUBE1 in human platelets. Cardiovasc Res (2006) 71:486–495.
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[Abstract/Free Full Text] - Lindemann S., Tolley N.D., Dixon D.A., McIntyre T.M., Prescott S.M., Zimmerman G.A., et al. Activated platelets mediate inflammatory signaling by regulated interleukin 1beta synthesis. J Cell Biol (2001) 154:485–490.
[Abstract/Free Full Text] - Ungerer M., Peluso M., Gillitzer A., Massberg S., Heinzmann U., Schulz C., et al. Generation of functional culture-derived platelets from CD34+progenitor cells to study transgenes in the platelet environment. Circ Res (2004) 95:e36–e44.
[Abstract/Free Full Text]
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