Postclotting Cellular Effects of Thrombin Mediated by Interaction with High-Affinity Thrombin Receptors

Carney, Darrell H.

doi:10.1007/978-1-4615-3296-5_10

Cited by 16 publications

(12 citation statements)

References 145 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Procoagulant a-thrombin (thrombin) has multiple biological effects in a variety of cell types and tissues (for reviews, see Carney, 1992;Coughlin et al, 1992). In CCL39 hamster fibroblasts, thrombin is a potent mitogenic factor.…”

Section: Introductionmentioning

confidence: 99%

Shc adaptor proteins are key transducers of mitogenic signaling mediated by the G protein-coupled thrombin receptor.

et al. 1996

View full text Add to dashboard Cite

The serine protease thrombin activates G protein signaling systems that lead to Ras activation and, in certain cells, proliferation. Whereas the steps leading to Ras activation by G protein‐coupled receptors are not well defined, the mechanisms of Ras activation by receptor tyrosine kinases have recently been elucidated biochemically and genetically. The present study was undertaken to determine whether common signaling components are used by these two distinct classes of receptors. Here we report that the adaptor protein Shc, is phosphorylated on tyrosine residues following stimulation of the thrombin receptor in growth‐responsive CCL39 fibroblasts. Shc phosphorylation by thrombin or the thrombin receptor agonist peptide is maximal by 15 min and persists for > or = 2 h. Following thrombin stimulation, phosphorylated Shc is recruited to Grb2 complexes. One or more pertussis toxin‐insensitive proteins appear to mediate this effect, since (i) pertussis toxin pre‐treatment of cells does not blunt the action of thrombin and (ii) Shc phosphorylation on tyrosine can be stimulated by the muscarinic m1 receptor. Shc phosphorylation does not appear to involve protein kinase C, since the addition of 4‐beta‐phorbol‐12,13‐dibutyrate has no effect. Rather, thrombin‐induced Shc phosphorylation is enhanced in cells depleted of phorbol ester‐sensitive protein kinase C isoforms. Expression of mutant Shc proteins defective in Grb2 binding displays a dominant‐negative effect on thrombin‐stimulated p44 MAP kinase activation, gene induction and cell growth. From these data, we conclude that Shc represents a crucial point of convergence between signaling pathways activated by receptor tyrosine kinases and G protein‐coupled receptors.

show abstract

Section: Introductionmentioning

confidence: 99%

Shc adaptor proteins are key transducers of mitogenic signaling mediated by the G protein-coupled thrombin receptor.

et al. 1996

View full text Add to dashboard Cite

show abstract

“…[17][18][19] Although many of the cellular effects of thrombin appear to require proteolytic activity and activation of proteolytically activated receptors, 20 studies show that binding of thrombin or thrombin derivatives without proteolytic activity promotes a number of cellular events involved in tissue repair and wound healing. [21][22][23][24] . These observations have led to the hypothesis that nonproteolytic peptide fragments of thrombin released from a fibrin clot during early stages of wound repair may modulate inflammation and promote healing.…”

mentioning

confidence: 99%

Thrombin peptide Chrysalin^® stimulates healing of diabetic foot ulcers in a placebo‐controlled phase I/II study

Fife

Mader

Stone³

et al. 2007

Wound Repair Regeneration

Self Cite

View full text Add to dashboard Cite

Thrombin and thrombin peptides play a role in initiating tissue repair. The potential safety and efficacy of TP508 (Chrysalin) treatment of diabetic foot ulcers was evaluated in a 60-subject, prospective, randomized, double-blind, placebo-controlled phase I/II clinical trial. Chrysalin in saline or saline alone was applied topically, twice weekly, to diabetic ulcers with standardized care and offloading. A dose-dependent effect was seen in the per-protocol population where 1 and 10 mug Chrysalin treatment resulted in 45 and 72% more subjects with complete healing than placebo treatment. Chrysalin treatment of foot ulcers more than doubled the incidence of complete healing (p<0.05), increased mean closure rate approximately 80% (p<0.05), and decreased the median time to 100% closure by approximately 40% (p<0.05). Chrysalin treatment of heel ulcers within this population resulted in mean closure rates 165% higher than placebos (p<0.02) and complete healing in 86% (6/7) of ulcers compared with 0% (0/5) of placebo ulcers (p<0.03). Local wound reactions and adverse events (AEs) were equal between groups with no reported drug-related changes in laboratory tests or serious AEs. These results indicate the potential safety and efficacy of Chrysalin for treatment of diabetic foot ulcers.

show abstract

“…This raises the possibility that TP508 may accelerate normal wound healing and/or overcome defects associated with healing failure in chronic wounds. Thrombin stimulates proliferative, migratory, and differentiative cellular responses that are involved in early stages of wound healing 2–4 . Some of these effects require thrombin's proteolytic activity, while others appear to be stimulated by non‐proteolytic interaction of thrombin or TP508 with high‐affinity receptors.…”

mentioning

confidence: 99%

Acceleration of full‐thickness wound healing in normal rats by the synthetic thrombin peptide, TP508

Stiernberg

Norfleet

Redin

et al. 2000

Wound Repair Regeneration

View full text Add to dashboard Cite

Thrombin is an essential factor in hemostasis, inflammation, and tissue repair. The synthetic thrombin peptide, TP508, binds to high-affinity thrombin receptors and mimics cellular effects of thrombin at sites of tissue injury. Treatment of full-thickness excisional wounds in normal rats with a single topical application of 0.1 microg TP508 (14 pmol/cm2) reproducibly accelerates wound closure, yielding wounds that on average close 39% more than controls by day 7 (p < 0.001). Wounds treated with 1.0 microg TP508 are 35% and 43% (p < 0.001) smaller than controls on day 7 and 10, respectively. The early rate of closure is approximately 40% greater in TP508-treated than vehicle-treated wounds (20 versus 14 mm2/day) and remains higher through day 7. Breaking strength after closure is slightly greater (15-23%) in wounds treated with TP508 than with saline alone. Histologic comparisons show that TP508 enhances recruitment of inflammatory cells to the wound site within 24 hours post-injury. TP508 treatment also augments revascularization of injured tissue, as evidenced at day 7 by the larger size of functional vessels in the granulation tissue and by the directed development of blood vessels to wounds. These studies raise the possibility that TP508 may be clinically useful in management of open wounds.

show abstract

Postclotting Cellular Effects of Thrombin Mediated by Interaction with High-Affinity Thrombin Receptors

Cited by 16 publications

References 145 publications

Shc adaptor proteins are key transducers of mitogenic signaling mediated by the G protein-coupled thrombin receptor.

Shc adaptor proteins are key transducers of mitogenic signaling mediated by the G protein-coupled thrombin receptor.

Thrombin peptide Chrysalin^® stimulates healing of diabetic foot ulcers in a placebo‐controlled phase I/II study

Acceleration of full‐thickness wound healing in normal rats by the synthetic thrombin peptide, TP508

Contact Info

Product

Resources

About

Postclotting Cellular Effects of Thrombin Mediated by Interaction with High-Affinity Thrombin Receptors

Cited by 16 publications

References 145 publications

Shc adaptor proteins are key transducers of mitogenic signaling mediated by the G protein-coupled thrombin receptor.

Shc adaptor proteins are key transducers of mitogenic signaling mediated by the G protein-coupled thrombin receptor.

Thrombin peptide Chrysalin® stimulates healing of diabetic foot ulcers in a placebo‐controlled phase I/II study

Acceleration of full‐thickness wound healing in normal rats by the synthetic thrombin peptide, TP508

Contact Info

Product

Resources

About

Thrombin peptide Chrysalin^® stimulates healing of diabetic foot ulcers in a placebo‐controlled phase I/II study