Transient potential receptor channel 4 controls thrombospondin‐1 secretion and angiogenesis in renal cell carcinoma

Veliceasa, Dorina; Ivanovic, Marina; Hoepfner, Frank Thilo Schulze; Thumbikat, Praveen; Volpert, Olga V.; Smith, Norm D.

doi:10.1111/j.1742-4658.2007.06159.x

Cited by 76 publications

(64 citation statements)

References 56 publications

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“…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. Indeed, Ca 2ϩ -binding sites have been shown to be important for proper folding of thrombospondins (20,27,32), and reduced Ca 2ϩ levels cause impaired secretion and retention of Thbs1 in the ER of renal cell carcinoma cells (55). However, the mCa 2ϩ mutant of Thbs4 still induced vesicular expansion, suggesting that while this mutant did not traverse the secretory pathway, it still functioned properly within the ER to facilitate Atf6␣ activation and downstream vesicular expansion.…”

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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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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“…In tadpole somitic mesoderm and skeletal muscle with TSP-5/COMP in the Golgi of chondrocytes from PSACH patients (see section ROLES OF TSPS IN VIVO), suggesting that these chaperones also participate in its normal quality control (Hecht et al 2001;Vranka et al 2001). Trafficking of TSPs from ER to Golgi appears to be by COPII vesicles (Veliceasa et al 2007). Sec23a-positive vesicles are implicated in trafficking wild-type TSP-5/COMP to the Golgi in chondrocytes (Fig.…”

Section: Tsp-4mentioning

confidence: 99%

The Thrombospondins

Adams¹,

Lawler²

2011

Cold Spring Harbor Perspectives in Biology

385

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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“…A previous study reported that loss of TRPC4 resulted in an impaired secretion of thrombospondin-1, which is an inhibitor of angiogenesis, from renal cell carcinoma and thus facilitated angiogenesis in the tumor environment. 49 Taken together, we propose that TRPCs regulate angiogenesis possibly via 2 nonexclusive mechanisms. First, TRPCs may function inside ECs to directly modulate their responses to anti-and/or proangiogenic factors.…”

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confidence: 99%

TRPC1 Is Essential for In Vivo Angiogenesis in Zebrafish

et al. 2010

Circulation Research

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Key Words: TRPC1 Ⅲ VEGF Ⅲ ISV Ⅲ angiogenesis Ⅲ zebrafish T he vascular system of vertebrates consists of a stereotyped and highly branched network of arteries, veins, and capillaries. This network extends into every tissue of the body and is tailored to its local physiological function. [1][2][3] The development of vascular networks requires 2 successive processes, vasculogenesis and angiogenesis. 1,2 During vasculogenesis, mesoderm-derived hemangioblasts differentiate in situ into endothelial cells (ECs), which coalesce at the midline to form a lumenized vascular plexus. 1,2 This primary network subsequently expands through angiogenesis, which is characterized by the growth of new blood vessels from preexisting ones. 1,2 Numerous ligands and their receptors have been identified to exert positive or negative regulation on angiogenesis, including vascular endothelial growth factor (VEGF)/ VEGF receptors, angiopoietin/Tie and notch/␦-like 4, [3][4][5][6][7][8] and their downstream signaling pathways have also been partially elucidated. [3][4][5][6][7] For example, VEGF-induced angiogenesis is mainly attributable to the activation of both Mitogen-activated protein kinase/extracellular signalregulated kinase (ERK)1/2 cascade and AKT/protein kinase B pathway. 9 Angiopoietin1/Tie2-induced EC migration during angiogenesis is largely mediated by the activation of phosphoinositide 3-kinase signaling pathway. 8 There is increasing evidence that guidance of vessels and nerves during development share common underlying mechanisms. [2][3][4][5][6]10,11 Some axon guidance molecules, such as ephrins, netrins, and slits, also influence angiogenic sprouting. 3,6,7,10,11 Recent studies have shown that Ca 2ϩ -permeable transient receptor potential type C channels (TRPCs) 12 are downstream effectors of the axon guidance molecules netrin-1, brain-derived neurotrophic factor and myelinassociated glycoprotein, and are required for axon guidance triggered by these cues. [13][14][15] The TRPC family is composed of 7 members in mammals (TRPC1 to -7). 12 In the vascular Original received March 19, 2009; resubmission received August 19, 2009; revised resubmission received February 10, 2010; accepted February 11, 2010. From [17][18][19] However, the role of TRPCs in vascular development remains largely unknown. The goal of this study is to investigate whether TRPCs are important for angiogenesis in vivo.The zebrafish has emerged as a powerful vertebrate model system for in vivo study of vascular development. 20 Transgenic lines with vascular ECs expressing fluorescent proteins allow imaging of blood vessel growth in live embryos. 21,22 Moreover, a range of reverse genetic methods, including the antisense morpholino oligonucleotide (MO)-based knockdown approach, 23,24 have been developed for manipulating gene expression and function in zebrafish. 25 Recently, zebrafish trpc1 was identified. It is highly homologous to mammalian trpc1 and ubiquitously expressed postfertilization until 24 hours. 26 In the present study, we examined the...

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Transient potential receptor channel 4 controls thrombospondin‐1 secretion and angiogenesis in renal cell carcinoma

Cited by 76 publications

References 56 publications

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

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

The Thrombospondins

TRPC1 Is Essential for In Vivo Angiogenesis in Zebrafish

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