Fibrinogen-Related Proteins in Tissue Repair: How a Unique Domain with a Common Structure Controls Diverse Aspects of Wound Healing

Abstract

Fibrinogen-related proteins (FRePs) comprise an intriguing collection of extracellular molecules, each containing a conserved fibrinogen-like globe (FBG). This group includes the eponymous fibrinogen as well as the tenascin, angiopoietin, and ficolin families. Many of these proteins are upregulated during tissue repair and exhibit diverse roles during wound healing. An increasing body of evidence highlights the specific expression of a number of FRePs following tissue injury and infection. Upon induction, each FReP uses its FBG domain to mediate quite distinct effects that contribute to different stages of tissue repair, such as driving coagulation, pathogen detection, inflammation, angiogenesis, and tissue remodeling. Despite a high degree of homology among FRePs, each contains unique sequences that enable their diversification of function. Comparative analysis of the structure and function of FRePs and precise mapping of regions that interact with a variety of ligands has started to reveal the underlying molecular mechanisms by which these proteins play very different roles using their common domain. Fibrinogen has long been used in the clinic as a synthetic matrix serving as a scaffold or a delivery system to aid tissue repair. Novel therapeutic strategies are now emerging that harness the use of other FRePs to improve wound healing outcomes. As we learn more about the underlying mechanisms by which each FReP contributes to the repair response, specific blockade, or indeed potentiation, of their function offers real potential to enable regulation of distinct processes during pathological wound healing.

Exploring the oncoproteomic response of human prostate cancer to therapeutic radiation using data‐independent acquisition (DIA) mass spectrometry

“…We posit that the increased abundance of these types of proteins is likely due to a combination of wound-healing responses and increased production of supportive tissue during a regenerative remodeling phase. [18][19][20] These observations were congruent with enriched ontologies amongst the conserved protein changes. Many of the ontologies that were enriched have well-described roles in processes known to be perturbed by ionising radiation, including cellular defence, 21,22 innate immune activation, 22 and initiation of the complement cascade.…”

“…Nevertheless, a small group of five glycoproteins, including tenascin C, fibronectin, and the complete fibrinogen hexamer (consisting of subunits α, β, and γ) complex, also known as factor I, were consistently more abundant and had the greatest magnitude of change. We posit that the increased abundance of these types of proteins is likely due to a combination of wound‐healing responses and increased production of supportive tissue during a regenerative remodeling phase . These observations were congruent with enriched ontologies amongst the conserved protein changes.…”

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“…7 Angiopoietins can promote angiogenesis, remodeling, maturation and maintenance through using a coiled-coil domain in the N-terminus and a fibrinogen-like domain in the C-terminus. 8 In addition, some angiopoietins are potent regulators of lipid, glucose, and energy metabolism.…”

Embracing the complexity of matricellular proteins: the functional and clinical significance of splice variation

“…The FBG domain is important for proteoglycan and integrin binding (94,95). It has also been suggested that the TNC FBG domain can activate TLR4, although it is not known whether this is a direct effect (96). It will therefore be of interest to further investigate the expression and function of this novel TNC variant.…”