Thrombospondin-4 and Cartilage Oligomeric Matrix Protein form Heterooligomers in Equine Tendon

Södersten, Fredrik; Ekman, Stina; Schmitz, Markus; Paulsson, Mats; Zaucke, Frank

doi:10.1080/03008200600584124

Cited by 35 publications

(33 citation statements)

References 28 publications

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“…Studies of bovine, equine and human TSP4 have shown that it localizes to tendons (Hauser et al, 1995; Chen et al, 2000; Södersten et al, 2006). To determine if the functional roles of zebrafish Tsp4b are evolutionarily conserved, we injected recombinant human TSP4 (2 ng/embryo) into the interstitial space between myofibers of 60 hpf Tsp4b-deficient embryos.…”

Section: Resultsmentioning

confidence: 99%

“…Because Tsps interact with other Itg ligands (e.g., Lam, Col, Fn) in vitro it has been debated as to whether Tsps play instructive or merely permissive roles in ECM organization and cell-ECM interactions (Narouz-Ott et al, 2000; Södersten et al, 2006; Tan and Lawler, 2009). In Drosophila , by virtue of its canonical RGD motif, Tsp plays a primary role as an Itg ligand in developing tendons.…”

Section: Discussionmentioning

confidence: 99%

“…Of the five vertebrate Tsp genes, subclass B including Tsp4 and Tsp5 have been observed in connective tissues associated with the musculoskeletal system (Hauser et al, 1995; Tucker et al, 1995; Hecht et al, 1998; Jelinsky et al, 2010; Frolova et al, 2014) and have been shown to function as homo- and hetero-pentamers through a conserved coiled-coil region (Hauser et al, 1995; Narouz-Ott et al, 2000; Södersten et al, 2006). Human TSP4 levels are highly elevated in patients with Duchenne muscular dystrophy (DMD), α-sarcoglycan deficiency, as well as in cardiac ECM in response to stress, and TSP5 levels increase during joint injury, osteoarthritis and cartilage degradation (Chen et al, 2000; Hecht et al, 1998; Timmons et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Thrombospondin-4 controls matrix assembly during development and repair of myotendinous junctions

Subramanian

Schilling

2014

eLife

117

131

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Tendons are extracellular matrix (ECM)-rich structures that mediate muscle attachments with the skeleton, but surprisingly little is known about molecular mechanisms of attachment. Individual myofibers and tenocytes in Drosophila interact through integrin (Itg) ligands such as Thrombospondin (Tsp), while vertebrate muscles attach to complex ECM fibrils embedded with tenocytes. We show for the first time that a vertebrate thrombospondin, Tsp4b, is essential for muscle attachment and ECM assembly at myotendinous junctions (MTJs). Tsp4b depletion in zebrafish causes muscle detachment upon contraction due to defects in laminin localization and reduced Itg signaling at MTJs. Mutation of its oligomerization domain renders Tsp4b unable to rescue these defects, demonstrating that pentamerization is required for ECM assembly. Furthermore, injected human TSP4 localizes to zebrafish MTJs and rescues muscle detachment and ECM assembly in Tsp4b-deficient embryos. Thus Tsp4 functions as an ECM scaffold at MTJs, with potential therapeutic uses in tendon strengthening and repair.DOI: http://dx.doi.org/10.7554/eLife.02372.001

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Thrombospondin-4 controls matrix assembly during development and repair of myotendinous junctions

Subramanian

Schilling

2014

eLife

117

131

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“…The mCa 2ϩ mutant may also serve as a dominant negative mutant for Thbs5/COMP, since Thbs4 and Thbs5/COMP can assemble as heteropentamers in vivo (54). Regardless, the lack of secretion by the mCa 2ϩ mutant suggests that Ca 2ϩ binding or the sensing of ER Ca 2ϩ is required for proper folding and/or trafficking of Thbs4.…”

Section: Discussionmentioning

confidence: 99%

Dissection of Thrombospondin-4 Domains Involved in Intracellular Adaptive Endoplasmic Reticulum Stress-Responsive Signaling

Brody

Schips

Vanhoutte

et al. 2016

Molecular and Cellular Biology

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bThrombospondins are a family of stress-inducible secreted glycoproteins that underlie tissue remodeling. We recently reported that thrombospondin-4 (Thbs4) has a critical intracellular function, regulating the adaptive endoplasmic reticulum (ER) stress pathway through activating transcription factor 6␣ (Atf6␣). In the present study, we dissected the domains of Thbs4 that mediate interactions with ER proteins, such as BiP (Grp78) and Atf6␣, and the domains mediating activation of the ER stress response. Functionally, Thbs4 localized to the ER and post-ER vesicles and was actively secreted from cardiomyocytes, as were the type III repeat (T3R) and TSP-C domains, while the LamG domain localized to the Golgi apparatus. We also mutated the major calcium-binding motifs within the T3R domain of full-length Thbs4, causing ER retention and secretion blockade. The T3R and TSP-C domains as well as wild-type Thbs4 and the calcium-binding mutant interacted with Atf6␣, induced an adaptive ER stress response, and caused expansion of intracellular vesicles. In contrast, overexpression of a related secreted oligomeric glycoprotein, Nell2, which lacks only the T3R and TSP-C domains, did not cause these effects. Finally, deletion of Atf6␣ abrogated Thbs4-induced vesicular expansion. Taken together, these data identify the critical intracellular functional domains of Thbs4, which was formerly thought to have only extracellular functions.

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“…Oligomerization of TSP-1 into trimers occurs through noncovalent association of the coiledcoil domains (Vischer et al 1985;Prabakaran et al 1996). Although TSPs are predominantly homooligomers, natural heteropentamers of TSP-4 and TSP-5/COMP subunits occur in tendon (Hecht et al 1998;Södersten et al 2006).…”

Section: Cell Biology Of Thrombospondins Expression and Synthesis Of mentioning

confidence: 99%

The Thrombospondins

Adams¹,

Lawler²

2011

Cold Spring Harbor Perspectives in Biology

403

416

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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 celldependent 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.T hrombospondins (TSPs) comprise a conserved family of extracellular, oligomeric, multidomain, calcium-binding glycoproteins. In general, basal metazoa and protostomes encode a single TSP in their genomes and deuterostomes have multiple TSP genes. The TSPs of mammals have many complex tissue-specific roles, including activities in wound healing and angiogenesis, vessel wall biology, connective tissue organization, and synaptogenesis. These activities derive mechanistically from interactions with cell surfaces, growth factors, cytokines, or components of the extracellular matrix (ECM) that collectively regulate many aspects of cell phenotype. Emerging evidence on the functions of TSPs in invertebrates suggests that ancient functions include bridging activities in cell-cell and cell-ECM interactions. Knowledge of TSP domain structures provides a rational basis for understanding their roles in vivo and associations with human disease and is assisting ongoing translational applications. DOMAIN ARCHITECTURE AND DOMAIN STRUCTURESThe domain architectures of representative TSP polypeptides are shown in Figure 1A. The invariant carboxy-terminal regions comprise a series of EGF-like domains, thirteen calcium-binding type 3 repeats, and a carboxy-terminal domain structurally homologous to the L-type lectin

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Thrombospondin-4 and Cartilage Oligomeric Matrix Protein form Heterooligomers in Equine Tendon

Cited by 35 publications

References 28 publications

Thrombospondin-4 controls matrix assembly during development and repair of myotendinous junctions

Thrombospondin-4 controls matrix assembly during development and repair of myotendinous junctions

Dissection of Thrombospondin-4 Domains Involved in Intracellular Adaptive Endoplasmic Reticulum Stress-Responsive Signaling

The Thrombospondins

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