A Novel TNF Receptor Family Member Binds TWEAK and Is Implicated in Angiogenesis

Wiley, Steven R.; Cassiano, Linda; Lofton, Timothy; Davis-Smith, Terry; Winkles, Jeffrey A.; Lindner, Volkhard; Hua, Liu; Daniel, Thomas O.; Smith, Craig A.; Fanslow, William C.

doi:10.1016/s1074-7613(01)00232-1

Cited by 352 publications

(382 citation statements)

References 23 publications

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“…Like other TNF family members, TWEAK seems to play different roles depending on the cellular context, ranging from apoptosis induction in transformed cells to stimulation of growth and migration in endothelial cells. Fn14 was recently identified as a fully functional TWEAK receptor (27). This small membrane protein is able to mediate a variety of intracellular signals in a cellspecific fashion including apoptosis, necrosis, proliferation, and survival (17,22,31,43).…”

Section: Discussionmentioning

confidence: 99%

“…DR3-independent signaling has been ascribed to a recently identified receptor for TWEAK, originally cloned as a mitogen-inducible gene in murine fibroblasts and named fibroblast growth factor-inducible 14 (Fn14) (27,28). Fn14 is distantly related to other members of the TNFR family and contains one cysteine-rich domain in the extracellular region and a TNFR-associated factor-binding domain in the cytoplasmic region (29,30).…”

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confidence: 99%

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Multiple Members of the TNF Superfamily Contribute to IFN-γ-Mediated Inhibition of Erythropoiesis

Felli

Pedini

Zeuner

et al. 2005

The Journal of Immunology

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IFN-γ inhibits the growth and differentiation of erythroid precursor cells and mediates hemopoietic suppression through mechanisms that are not completely understood. We found that treatment of human erythroid precursor cells with IFN-γ up-regulates the expression of multiple members of the TNF family, including TRAIL and the recently characterized protein TWEAK. TWEAK and its receptor fibroblast growth factor-inducible 14 (Fn14) were expressed by purified erythroblasts at all the stages of maturation. Exposure to recombinant TWEAK or agonist anti-Fn14 Abs was able to inhibit erythroid cell growth and differentiation through caspase activation. Because other members of the TNF family such as TRAIL and CD95 ligand (CD95L) are known to interfere with erythroblast growth and differentiation, we investigated the role of different TNF/TNFR family proteins as potential effectors of IFN-γ in the immature hemopoietic compartment. Treatment of erythroid precursor cells with agents that blocked either TRAIL, CD95L, or TWEAK activity was partially able to revert the effect of IFN-γ on erythroid proliferation and differentiation. However, the simultaneous inhibition of TRAIL, TWEAK, and CD95L resulted in a complete abrogation of IFN-γ inhibitory effects, indicating the requirement of different receptor-mediated signals in IFN-γ-mediated hemopoietic suppression. These results establish a new role for TWEAK and its receptor in normal and IFN-γ-mediated regulation of hematopoiesis and show that the effects of IFN-γ on immature erythroid cells depend on multiple interactions between TNF family members and their receptors.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Multiple Members of the TNF Superfamily Contribute to IFN-γ-Mediated Inhibition of Erythropoiesis

Felli

Pedini

Zeuner

et al. 2005

The Journal of Immunology

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“…The potential biological role of TWEAK and FN14 in the wound response of normal tissues was initially supported by several studies demonstrating that TWEAK is angiogenic 1,11,12 and that FN14 expression is elevated in the proliferating endothelial and smooth muscle cells of damaged rat arteries. 1 More recently it has been shown that TWEAK can associate with another novel secreted angiogenic factor, VG5Q, which is mutated in the vascular disease KlippelTrenaunay syndrome, 13 but, the biological significance of this interaction has yet to be elucidated.…”

mentioning

confidence: 98%

“…The TNF superfamily (TNSF) receptor FN14 has a small cytoplasmic domain, and the limited similarity of its extracellular domain to the cysteine-rich domains of the TNFSF receptors was only appreciated retrospectively when it was discovered that it bound TWEAK. 1 Recent work has demonstrated that TWEAK knockout animals have an activated immune system that is skewed by elevated numbers of natural killer (NK) cells and responds lethally to bacterial endotoxins, but also shows a powerful ability to prevent tumour growth. 2 Other topical papers show that TWEAK and FN14 work to promote liver regeneration following injury and prevent the differentiation of a diverse range of cell types.…”

mentioning

confidence: 99%

“…1 More recently it has been shown that TWEAK can associate with another novel secreted angiogenic factor, VG5Q, which is mutated in the vascular disease KlippelTrenaunay syndrome, 13 but, the biological significance of this interaction has yet to be elucidated. TWEAK and FN14 have also been implicated in promoting cellular proliferation and inhibiting differentiation.…”

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TWEAK shall inherit the earth

Vince

Silke

2006

Cell Death Differ

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Sometimes size really does not matter: recent papers on the tumour necrosis factor (TNF)-like ligand, TWEAK (tumour necrosis factor-like weak inducer of apoptosis), and its diminutive 129 amino-acid receptor, FN14 (fibroblast growth factor (FGF) -inducible 14 kDa protein), describe an impressive and potent range of biological effects. The TNF superfamily (TNSF) receptor FN14 has a small cytoplasmic domain, and the limited similarity of its extracellular domain to the cysteine-rich domains of the TNFSF receptors was only appreciated retrospectively when it was discovered that it bound TWEAK. 1 Recent work has demonstrated that TWEAK knockout animals have an activated immune system that is skewed by elevated numbers of natural killer (NK) cells and responds lethally to bacterial endotoxins, but also shows a powerful ability to prevent tumour growth. 2 Other topical papers show that TWEAK and FN14 work to promote liver regeneration following injury and prevent the differentiation of a diverse range of cell types. The role of TWEAK and FN14 in cancer has yet to be conclusively established, but several groups have observed high expression of FN14 in cancerous tissues, and demonstrated that it can promote cellular functions important for tumorigenesis, including cytokine production, cellular proliferation, survival, migration and angiogenesis. 3 TWEAK is a type II transmembrane protein (extracellular C-terminus) that can undergo proteolysis to produce an active soluble homotrimer, 4,5 whereas FN14 is a type Ia transmembrane protein. 6 In some respects the potent effects of the ligand TWEAK are reminiscent to those of TNFa: both factors appear to play roles in inflammation, and both have the capacity to induce cell death, although usually in conjunction with another stimulus. Responses to TNFSF ligands can be complex because several ligands often bind to the same receptor and vice versa. For example, both the human ligands TNFa and LTa bind the receptors TNFR1 and TNFR2, whereas LTa also binds HVEM. In fact, more than half of the TNSF ligands bind to at least two receptors. 7 One of the amazing things about the TWEAK/FN14 system is that it is a simple, single ligand, single receptor system 7 in which the intracellular signalling domain of FN14 is only 28 amino acids. It remains possible that another TWEAK receptor exists 8 which might help to explain the diverse range of effects that TWEAK produces, but this is yet to be conclusively established.

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Soluble TWEAK is markedly elevated in hemophagocytic lymphohistiocytosis

et al. 2007

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Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a newly identified monocyte derived cytokine, which has weak apoptosis inducing function against sensitive tumor cell lines in vitro. Also, TWEAK has been reported to have proangiogenic and proinflammatory activities in vivo. However, its functions in pathological situation remain to be elucidated. Here, we analyzed soluble TWEAK in serum of 24 patients with hemophagocytic lymphohistiocytosis (HLH) in combination with interferon-c (IFN-c) and killer-specific secretory protein of 37 kDa (Ksp37). Soluble TWEAK was not detected in serum of healthy individuals. Soluble TWEAK was markedly elevated in all six primary HLH patients and 12 of 18 secondary HLH patients. Serum IFN-c, which is an only known mediator to stimulate TWEAK production in monocyte in vitro, was not elevated despite elevated serum TWEAK in three of six primary HLH patients, although IFN-c was markedly elevated in other cases. Ksp37 was only slightly increased in HLH patients. These results indicate that TWEAK may be involved in pathogenesis of HLH and is useful as a clinical marker. Am. J. Hematol. 83:222-225, 2008. V

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A Novel TNF Receptor Family Member Binds TWEAK and Is Implicated in Angiogenesis

Cited by 352 publications

References 23 publications

Multiple Members of the TNF Superfamily Contribute to IFN-γ-Mediated Inhibition of Erythropoiesis

Multiple Members of the TNF Superfamily Contribute to IFN-γ-Mediated Inhibition of Erythropoiesis

TWEAK shall inherit the earth

Soluble TWEAK is markedly elevated in hemophagocytic lymphohistiocytosis

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