Thrombospondin-4 in tissue remodeling

Abstract

Thrombospondin-4 (TSP-4) belongs to the thrombospondin protein family that consists of five highly homologous members. A number of novel functions have been recently assigned to TSP-4 in cardiovascular and nervous systems, inflammation, cancer, and the motor unit, which have attracted attention to this extracellular matrix (ECM) protein. These newly discovered functions set TSP-4 apart from other thrombospondins. For example, TSP-4 promotes angiogenesis while other TSPs either prevent it or have no effect on new blood vessel growth; TSP-4 reduces fibrosis and collagen production while TSP-1 and TSP-2 promote fibrosis in several organs; unlike other TSPs, TSP-4 appears to have some structural functions in ECM. The current information about TSP-4 functions in different organs and physiological systems suggests that this evolutionary conserved protein is a major regulator of the extracellular matrix (ECM) organization and production and tissue remodeling during the embryonic development and response to injury. In this review article, we summarize the properties and functions of TSP-4 and discuss its role in tissue remodeling.

Keywords: Angiogenesis; Extracellular matrix (ECM); Fibrosis; Myocardium; Nociception; Skeletal muscle.

Figure 1. Domain structure of TSP-4 and its interaction with cells and ECM

A: Domains of a TSP-4 monomer; B: TSP-4 is a pentamer; C: The pentameric structure allows TSP-4 to engage in multiple interactions with cells and proteins in ECM through binding sites in heparin-binding N-terminal domain, EGF-like domains, and conserved L-lectin C-terminal domain. Binding sites for the cellular receptors are marked with red dots (e.g., heparan sulfates, integrins α_vβ₃, and α_Mβ₂, gabapentin receptor α₂δ-1); binding sites for ECM proteins are marked with green dots. There are both the ECM ligands binding the L-lectin domain (shown in pink), and ligands with binding sites in other domains of TSP-4, e.g., in EGF-like domains (shown in brown). Thus, a single molecule of TSP-4 can simultaneously engage multiple cellular receptors and ECM ligands and organize ECM and the interaction of the cells with ECM.