Transforming growth factor βs and wound healing

O’Kane, Sharon; Ferguson, M. W. J.

doi:10.1016/s1357-2725(96)00120-3

Cited by 602 publications

(429 citation statements)

References 94 publications

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“…4), they often cause distinct outcomes in embryonic and adult tissues (17,19,21,30). These differences in TGF-␤s actions might be caused by their distinct interactions with their receptors.…”

Section: Tgf-␤1 -␤2 and -␤3 Exhibit Distinct Receptor Preferences Bmentioning

confidence: 99%

Ternary Complex of Transforming Growth Factor-β1 Reveals Isoform-specific Ligand Recognition and Receptor Recruitment in the Superfamily

Radaev

Zou

Huang

et al. 2010

Journal of Biological Chemistry

141

198

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Transforming growth factor (TGF)-␤1, -␤2, and -␤3 are 25-kDa homodimeric polypeptides that play crucial nonoverlapping roles in embryogenesis, tissue development, carcinogenesis, and immune regulation. Here we report the 3.0-Å resolution crystal structure of the ternary complex between human TGF-␤1 and the extracellular domains of its type I and type II receptors, T␤RI and T␤RII. The TGF-␤1 ternary complex structure is similar to previously reported TGF-␤3 complex except with a 10°rotation in T␤RI docking orientation. Quantitative binding studies showed distinct kinetics between the receptors and the isoforms of TGF-␤. T␤RI showed significant binding to TGF-␤2 and TGF-␤3 but not TGF-␤1, and the binding to all three isoforms of TGF-␤ was enhanced considerably in the presence of T␤RII. The preference of TGF-␤2 to T␤RI suggests a variation in its receptor recruitment in vivo. Although TGF-␤1 and TGF-␤3 bind and assemble their ternary complexes in a similar manner, their structural differences together with differences in the affinities and kinetics of their receptor binding may underlie their unique biological activities. Structural comparisons revealed that the receptor-ligand pairing in the TGF-␤ superfamily is dictated by unique insertions, deletions, and disulfide bonds rather than amino acid conservation at the interface. The binding mode of T␤RII on TGF-␤ is unique to TGF-␤s, whereas that of type II receptor for bone morphogenetic protein on bone morphogenetic protein appears common to all other cytokines in the superfamily. Further, extensive hydrogen bonds and salt bridges are present at the high affinity cytokine-receptor interfaces, whereas hydrophobic interactions dominate the low affinity receptor-ligand interfaces.Transforming growth factor (TGF)-␤ 2 isoforms regulate the growth and differentiation of many cell types involved in normal development, immune function, and carcinogenesis (1-3). TGF-␤s are the founding members of a highly diversified family of signaling ligands and receptors, known as the TGF-␤ superfamily. To date the superfamily consists of more than 30 growth factors and cytokines, including TGF-␤s, bone morphogenetic proteins (BMPs), activins, inhibins, nodal, Müllerian inhibiting substance, growth differentiation factors, and others (4). TGF-␤s and related factors signal through two single-pass transmembrane receptors, known as the type I and type II receptors. These two receptor types have the same overall domain structure, including an extracellular ligand-binding domain displaying a three-finger toxin fold, a single transmembrane helix, and a cytosolic serine-threonine kinase domain. Signaling is initiated by the ligand, which binds the receptor extracellular domains, bringing them together and triggering a phosphorylation cascade, whereby the type II phosphorylates the type I, and the type I phosphorylates Smads, the cytoplasmic effectors of the pathway (3).Specificities have been determined based on cell-based affinity labeling studies with radiolabeled ligands and have enabled th...

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Section: Tgf-␤1 -␤2 and -␤3 Exhibit Distinct Receptor Preferences Bmentioning

confidence: 99%

Ternary Complex of Transforming Growth Factor-β1 Reveals Isoform-specific Ligand Recognition and Receptor Recruitment in the Superfamily

Radaev

Zou

Huang

et al. 2010

Journal of Biological Chemistry

141

198

View full text Add to dashboard Cite

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“…On the contrary, in loss-offunction mutants of tkv, put, and schnurri, the cells of the LE still elongate, while those of the lateral ectoderm do not, indicating that the Dpp signal emanating from the LE cells is necessary for the elongation of the adja-cent ectodermal cells, but not for the elongation of the LE cells themselves (Knust 1997). Although the JNK signaling pathway has not been directly implicated in wound repair in mammalian systems, it should be noted that a pivotal role for TGF-␤ in the tissue-repair process is well documented (Grande 1997;Martin 1997;O'Kane and Ferguson 1997;Massague 1999;Ashcroft and Roberts 2000).…”

Section: Dorsal Closure In Drosophila As a Model System For Wound Repairmentioning

confidence: 99%

Role of Rho family GTPases in epithelial morphogenesis

Aelst¹,

Symons²

2002

Genes Dev.

213

184

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“…[135][136][137] Disturbances in the finely balanced ratio between the different members of the TGF-␤ superfamily lead to scarring and fibrosis. 138 The topical application of TGF-␤ to skin wounds results in increased breaking strength and accelerated wound healing. 139 TGF-␤ 3 inhibits cell cycle progression through G1.…”

Section: Transforming Growth Factor Beta (Tgf-␤)mentioning

confidence: 99%

Prophylaxis and treatment of chemo- and radiotherapy-induced oral mucositis – are there new strategies?

Karthaus

Rosenthal

Ganser

1999

Bone Marrow Transplant

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Summary:Oral mucositis is a major dose-limiting toxic effect of intensive cancer chemotherapy. Oral complications may lead to dose reduction or delay in further cancer treatment. Mucositis can be caused directly by cytotoxic effects and indirectly by sustained neutropenia after cytostatic therapy. An impaired mucosal barrier predisposes to life-threatening septic complications during aplasia. The prevalence of an oral focus in febrile neutropenia has been reported in up to 30% of cases and also reduces quality of life. The basic strategies aim at pain relief and prevention of bacterial and fungal infectious complications. However, no effective causal prophylaxis or treatment of oral mucositis is widely accepted. The introduction of cytokines, eg granulocytemacrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) for oral mucositis may be particularly effective and offer a new and hopeful approach. At present, the optimal growth factor, best schedule, effective dosage and best mode of application is not known.

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Transforming growth factor βs and wound healing

Cited by 602 publications

References 94 publications

Ternary Complex of Transforming Growth Factor-β1 Reveals Isoform-specific Ligand Recognition and Receptor Recruitment in the Superfamily

Ternary Complex of Transforming Growth Factor-β1 Reveals Isoform-specific Ligand Recognition and Receptor Recruitment in the Superfamily

Role of Rho family GTPases in epithelial morphogenesis

Prophylaxis and treatment of chemo- and radiotherapy-induced oral mucositis – are there new strategies?

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