Structures of thrombospondins.
Ontology highlight
ABSTRACT:
SUBMITTER: Carlson CB
PROVIDER: S-EPMC2578829 | biostudies-literature | 2008 Mar
REPOSITORIES: biostudies-literature
Publications
Structures of thrombospondins.
Carlson C B CB Lawler J J Mosher D F DF
Cellular and molecular life sciences : CMLS 20080301 5
Thrombospondins are large secreted, multimodular, calcium-binding glycoproteins that have complex roles in mediating cellular processes. Determination of high-resolution structures of thrombospondins has revealed unique and interesting protein motifs. Here, we review this progress and discuss implications for function. By combining structures of modules from thrombospondins and related extracellular proteins it is now possible to prepare an overall model of the structure of thrombospondin-1 and ...[more]
Similar Datasets
Project description:Thrombospondins are evolutionarily conserved, calcium-binding glycoproteins that undergo transient or longer-term interactions with other extracellular matrix components. They share properties with other matrix molecules, cytokines, adaptor proteins, and chaperones, modulate the organization of collagen fibrils, and bind and localize an array of growth factors or proteases. At cell surfaces, interactions with an array of receptors activate cell-dependent signaling and phenotypic outcomes. Through these dynamic, pleiotropic, and context-dependent pathways, mammalian thrombospondins contribute to wound healing and angiogenesis, vessel wall biology, connective tissue organization, and synaptogenesis. We overview the domain organization and structure of thrombospondins, key features of their evolution, and their cell biology. We discuss their roles in vivo, associations with human disease, and ongoing translational applications. In many respects, we are only beginning to appreciate the important roles of these proteins in physiology and pathology.
| S-EPMC3179333 | biostudies-literature
Project description:Thrombospondin-1 (TSP-1) was studied in the 1980s as a major component of platelet alpha-granules released upon platelet activation and also as a cell adhesion molecule. In 1993, we published a short review that discussed the exciting identification by molecular cloning of four additional vertebrate gene products related to TSP-1 [Current Biology 3 (1993) 188]. We put forward a structurally based classification for the newly identified proteins and discussed the functional and evolutionary implications of the new gene family. Since that time, the depth and breadth of knowledge on vertebrate TSPs and their functions in cells and tissues in health and disease has expanded into important new areas. Of particular interest is the new knowledge on the complex, domain and cell-type specific effects of TSPs on cell-signaling and cell-adhesion behaviour, the roles of TSP-1 and TSP-2 as anti-angiogenic agents, the roles of TSP-1 and TSP-2 in wound-healing, and associations of point mutations and polymorphisms in TSP-1, TSP-4 and TSP-5/COMP with human genetic diseases. The TSP family also now includes invertebrate members. In this article, we give the 2004 view on TSPs and our perspectives on the significant challenges that remain. Other articles in this issue discuss the functions of vertebrate TSPs in depth.
| S-EPMC2885884 | biostudies-literature
Project description:Thrombospondins (TSPs) represent extracellular matrix (ECM) proteins belonging to the TSP family that comprises five members. All TSPs have a complex multidomain structure that permits the interaction with various partners including other ECM proteins, cytokines, receptors, growth factors, etc. Among TSPs, TSP1, TSP2, and TSP4 are the most studied and functionally tested. TSP1 possesses anti-angiogenic activity and is able to activate transforming growth factor (TGF)-?, a potent profibrotic and anti-inflammatory factor. Both TSP2 and TSP4 are implicated in the control of ECM composition in hypertrophic hearts. TSP1, TSP2, and TSP4 also influence cardiac remodeling by affecting collagen production, activity of matrix metalloproteinases and TGF-? signaling, myofibroblast differentiation, cardiomyocyte apoptosis, and stretch-mediated enhancement of myocardial contraction. The development and evaluation of TSP-deficient animal models provided an option to assess the contribution of TSPs to cardiovascular pathology such as (myocardial infarction) MI, cardiac hypertrophy, heart failure, atherosclerosis, and aortic valve stenosis. Targeting of TSPs has a significant therapeutic value for treatment of cardiovascular disease. The activation of cardiac TSP signaling in stress and pressure overload may be therefore beneficial.
| S-EPMC5536028 | biostudies-literature
Project description:The extracellular matrix (ECM) is a complex, multiprotein network that has essential roles in tissue integrity and intercellular signaling in the metazoa. Thrombospondins (TSPs) are extracellular, calcium-binding glycoproteins that have biologically important roles in mammals in angiogenesis, vascular biology, connective tissues, immune response, and synaptogenesis. The evolution of these complex functional properties is poorly understood. We report here on the evolution of TSPs and their ligand-binding capacities, from comparative genomics of species representing the major phyla of metazoa and experimental analyses of the oligomerization properties of noncanonical TSPs of basal deuterostomes. Monomeric, dimeric, trimeric, and pentameric TSPs have arisen through separate evolutionary events involving gain, loss, or modification of a coiled-coil domain or distinct domains at the amino-terminus. The relative transience of monomeric forms under evolution implicates a biological importance for multivalency of the C-terminal region of TSPs. Most protostomes have a single TSP gene encoding a pentameric TSP. The pentameric form is also present in deuterostomes, and gene duplications at the origin of deuterostomes and gene loss and further gene duplication events in the vertebrate lineage gave rise to distinct forms and novel domain architectures. Parallel analysis of the major ligands of mammalian TSPs revealed that many binding activities are neofunctions representing either coevolutionary innovations in the deuterostome lineage or neofunctions of ancient molecules such as CD36. Contrasting widely conserved capacities include binding to heparan glycosaminoglycans, fibrillar collagen, or RGD-dependent integrins. These findings identify TSPs as fundamental components of the extracellular interaction systems of metazoa and thus impact understanding of the evolution of ECM networks. The widely conserved activities of TSPs in binding to ECM components or PS2 clade integrins will be relevant to use of TSPs in synthetic extracellular matrices or tissue engineering. In contrast, the neofunctions of vertebrate TSPs likely include interactions suitable for therapeutic targeting without general disruption of ECM.
| S-EPMC3107593 | biostudies-literature
Project description:The molecular processes underlying regeneration remain largely unknown. Several potential factors have been elucidated by focusing on the regenerative function of genes originally identified in a developmental context. A complementary approach is to consider the roles of factors involved in wound healing. Here we focus on the Thrombospondins, a family of secreted extracellular matrix proteins that have been implicated in skin wound healing in mammals. We show that a subset of Thrombospondins are expressed at distinct times and in particular cell types during axolotl limb regeneration. Our studies have revealed the axolotl orthologs of thrombospondin-1 (tsp-1) and thrombospondin-4 (tsp-4) are highly upregulated during limb regeneration in patterns both distinct and similar to larval limb development. Our data suggest that thrombospondins may be key regulators of limb regeneration in axolotl, while their activation appears to be relegated solely to wound healing in vertebrates that have lost the ability to regenerate limbs.
| S-EPMC3081376 | biostudies-literature
Project description:Thrombospondins participate in many aspects of tissue organization in adult tissue homeostasis, and their dysregulation contributes to pathological processes such as fibrosis and tumor progression. The incorporation of thrombospondins into extracellular matrix (ECM) as discrete puncta has been documented in various tissue and cell biological contexts, yet the underlying mechanisms remain poorly understood. We find that collagen fibrils are disorganized in multiple tissues of Thbs1(-/-) mice. In investigating how thrombospondins become retained within ECM and thereby affect ECM organization, we find that accumulation of thrombospondin-1 or thrombospondin-5 puncta within cell-derived ECM is controlled by a novel, conserved, surface-exposed site on the thrombospondin L-type lectin domain. This site acts to recruit thrombospondin molecules into ECM by intermolecular interactions in trans. This mechanism is fibronectin independent, can take place extracellularly, and is demonstrated to be direct in vitro. The trans intermolecular interactions can also be heterotypic-for example, between thrombospondin-1 and thrombospondin-5. These data identify a novel concept of concentration-dependent, intermolecular "matrix trapping" as a conserved mechanism that controls the accumulation and thereby the functionality of thrombospondins in ECM.
| S-EPMC4501361 | biostudies-literature
Project description:Thrombospondins (TSPs) -1 and -2 were among the first protein inhibitors of angiogenesis to be identified, a property that was subsequently attributed to the interactions of sequences in their type I repeats with endothelial cell-surface receptors. The interactions of TSPs-1 and -2 with cell-surface receptors, proteases, growth factors, and other bioactive molecules, coupled with the absence of direct structural functions that can be attributed to these matrix proteins, qualify them for inclusion in the category of 'matricellular proteins'. The phenotypes of TSP-1, TSP-2, and double TSP-1/2-null mice confirm the roles that these proteins play in the regulation of angiogenesis, and provide clues to some of the other important functions of these multi-domain proteins. One of these functions is the ability of TSP-1 to activate the latent TGFbeta1 complex, a property that is not shared by TSP-2. A major pathway by which TSP1 or TSP2 inhibits angiogenesis involves an interaction with CD 36 on endothelial cells, which leads to apoptosis of both the liganded and adjacent cells. However a homeostatic mechanism, which inhibits endothelial cell proliferation, and may be physiologically preferable under some circumstances, has also been elucidated, and involves interaction with the very low density lipoprotein receptor (VLDLR). The interaction of TSP1with its receptor, CD47, further inhibits angiogenesis by antagonizing nitric oxide signaling in endothelial and vascular smooth muscle cells. Paradoxically, there is also evidence that TSP-1 can function to promote angiogenesis. This apparent contradiction can be explained by the presence of sequences in different domains of the protein that interact with different receptors on endothelial cells. The anti-angiogenic function of TSPs has spurred interest in their use as anti-tumor agents. Currently, peptide mimetics, based on sequences in the type I repeats of TSPs that have been shown to have anti-angiogenic properties, are undergoing clinical testing.
| S-EPMC2778581 | biostudies-other
Project description:Nitric oxide (NO) maintains cardiovascular health by activating soluble guanylate cyclase (sGC) to increase cellular cGMP levels. Cardiovascular disease is characterized by decreased NO-sGC-cGMP signaling. Pharmacological activators and stimulators of sGC are being actively pursued as therapies for acute heart failure and pulmonary hypertension. Here we review molecular mechanisms that modulate sGC activity while emphasizing a novel biochemical pathway in which binding of the matricellular protein thrombospondin-1 (TSP1) to the cell surface receptor CD47 causes inhibition of sGC. We discuss the therapeutic implications of this pathway for blood flow, tissue perfusion, and cell survival under physiologic and disease conditions.
| S-EPMC3983488 | biostudies-literature
Project description:Thrombopoietic cells may differentially promote or inhibit tissue vascularization by releasing both pro- and antiangiogenic factors. However, the molecular determinants controlling the angiogenic phenotype of thrombopoietic cells remain unknown. Here, we show that expression and release of thrombospondins (TSPs) by megakaryocytes and platelets function as a major antiangiogenic switch. TSPs inhibited thrombopoiesis, diminished bone marrow microvascular reconstruction following myelosuppression, and limited the extent of revascularization in a model of hind limb ischemia. We demonstrate that thrombopoietic recovery following myelosuppression was significantly enhanced in mice deficient in both TSP1 and TSP2 (TSP-DKO mice) in comparison with WT mice. Megakaryocyte and platelet levels in TSP-DKO mice were rapidly restored, thereby accelerating revascularization of myelosuppressed bone marrow and ischemic hind limbs. In addition, thrombopoietic cells derived from TSP-DKO mice were more effective in supporting neoangiogenesis in Matrigel plugs. The proangiogenic activity of TSP-DKO thrombopoietic cells was mediated through activation of MMP-9 and enhanced release of stromal cell-derived factor 1. Thus, TSP-deficient thrombopoietic cells function as proangiogenic agents, accelerating hemangiogenesis within the marrow and revascularization of ischemic hind limbs. As such, interference with the release of cellular stores of TSPs may be clinically effective in augmenting neoangiogenesis.
| S-EPMC1679710 | biostudies-literature
Project description:Background/aimsArteries and veins modulate cardiovascular homeostasis and contribute to hypertension pathogenesis. Functional differences between arteries and veins are based upon differences in gene expression. To better characterize these expression patterns, and to identify candidate genes that could be manipulated selectively in the venous system, we performed whole genome expression profiling of arteries and veins.MethodsWe used the CodeLink platform and the major artery (thoracic aorta) and vein (caudal vena cava) of the rat.ResultsThe most prominent difference was pancreatitis-associated protein (PAP1), expressed 64-fold higher in vena cava versus aorta. Expression of mRNA for thrombospondins (TSP-1, TSP-4) was greater than 5-fold higher in veins versus arteries. Higher mRNA expression of TSP-1, TSP-2, TSP-4 and PAP1 in vena cava versus aorta was confirmed by PCR. Immunohistochemical analysis of tissue sections qualitatively confirmed a higher expression of these proteins in vena cava versus aorta.ConclusionThis is the first gene array study of adult rat arterial and venous tissues, and also the first study to report differences in inflammatory genes between arteries and veins. Data from these studies may provide novel insights into the genetic basis for functional differences between arteries and veins in health and disease.
| S-EPMC4327871 | biostudies-literature