Vitronectin—Master controller or micromanager?

Abstract

The concept that the mammalian glycoprotein vitronectin acts as a biological 'glue' and key controller of mammalian tissue repair and remodelling activity is emerging from nearly 50 years of experimental in vitro and in vivo data. Unexpectedly, the vitronectin-knockout (VN-KO) mouse was found to be viable and to have largely normal phenotype. However, diligent observation revealed that the VN-KO animal exhibits delayed coagulation and poor wound healing. This is interpreted to indicate that VN occupies a role in the earliest events of thrombogenesis and tissue repair. VN is the foundation upon which the thrombus grows in an organised structure. In addition to sealing the wound, the thrombus also serves to protect the underlying tissue from oxidation, is a reservoir of mitogens and tissue repair mediators, and provides a provisional scaffold for the repairing tissue. In the absence of VN (e.g., VN-KO animal), this cascade is disrupted before it begins. A wide variety of biologically active species associate with VN. Although initial studies were focused on mitogens, other classes of bioactives (e.g., glycosaminoglycans and metalloproteinases) are now also known to specifically interact with VN. Although some interactions are transient, others are long-lived and often result in multi-protein complexes. Multi-protein complexes provide several advantages: prolonging molecular interactions, sustaining local concentrations, facilitating co-stimulation of cell surface receptors and thereby enhancing cellular=biological responses. We contend that these, or equivalent, multi-protein complexes facilitate VN polyfunctionality in vivo. It is also likely that many of the species demonstrated to associate with VN in vitro, also associate with VN in vivo in similar multi-protein complexes. Thus, the predominant biological function of VN is that of a master controller of the extracellular environment; informing, and possibly instructing cells 'where' to behave, 'when' to behave and 'how' to behave (i.e., appropriately for the current circumstance). V C 2013 IUBMB Life, 65(10): [807][808][809][810][811][812][813][814][815][816][817][818] 2013

Vitronectin as a Micromanager of Cell Response in Material‐Driven Fibronectin Nanonetworks

“…The positively charged heparin‐binding domain of VN might then interact with the domains exposed by FN, allowing for a conformational transition of VN from its folded state, which aligns the amino‐terminal acidic domains containing the RGD motif with the heparin‐binding domain, into an extended form. [[qv: 5b]] Despite this lack of direct interaction, the behavior observed here is in line with reports indicating that, in vivo, the function of the protein is influenced and determined by its interactions with other species 1. For example, Peterson et al showed that the interaction of VN with plasminogen activator inhibitor type 1 during hemostatic processes alters the adhesive functions of VN, enhancing its cell/matrix‐binding properties as it multimerizes and is incorporated into higher order complexes 37.…”

“…We have also observed that other proteins or protein fragments affect this material‐driven FN assembly,20, 28 and we have identified VN as a promising candidate to alter FN organization at the cell–material interface 20. VN is in fact a low‐molecular‐weight matricellular component of the ECM and main adhesive component of serum, known to organize and micromanage the local hydrogel milieu in vivo through interactions with several other ECM molecules;1 indeed, it forms multiprotein complexes with a repertoire of biologically active species, modulating their biological functions. Here, we elucidate its role and interactions in an artificial fibrillar matrix which mimics a physiological ECM ( Figures 1A and 8 A).…”

“…This enhanced and organized availability cannot be ascribed to a change in the amount of adsorbed VN (VN surface density diminishes during co‐adsorption, Figure 1D), suggesting that the protein undergoes conformational reorganization following its interaction with FN. VN is known to interact with the extracellular matrix through its collagen‐ and heparin‐binding domains, but has not been reported to interact directly with FN in vivo 1, 34. Electrostatic interactions, which have been suggested to drive FN fibrillogenesis on negatively charged material surfaces,35 might influence the affinity between the two adsorbing species and ultimately affect their structural organization.…”

“…The design of this interface relies on the mimicry of the physical and biochemical cues of extracellular matrices (ECMs) that are encountered in vivo and regulate cell behavior, including phenomena like adhesion, migration, proliferation, and differentiation. Like other proteins that constitute physiological ECMs, vitronectin (VN) has a plethora of functions in tissue repair and homeostatic processes, including remodeling, and has been recently indicated as a biological “superglue.”1 This 75 kDa adhesive glycoprotein is a substantial component of plasma (≈300 µg mL −1 )2 and is also found in the extracellular space of different tissues. Contrary to other ECM proteins with structural functions, like collagens, fibronectin (FN) or laminin, VN is a “matricellular” protein: its functions depend on the interaction with other species, including matrix proteins, cell‐surface receptors, or other molecules such as cytokines 3.…”

Antagonists of IGF:Vitronectin Interactions Inhibit IGF-I–Induced Breast Cancer Cell Functions

“…For instance, ligand occupancy of integrins (receptors for ECM proteins) promotes phosphorylation and activity of the IGF-1R (8) and affects IGF and integrin signaling mediated by IRS-1, Shc, PI3K, and MAPK (9). There is also significant evidence that growth factors and ECM proteins interact (10), facilitating local storage of growth factors (11) in a "bioavailable" form. This localizes ligands in close proximity to their cognate cell surface receptors, thereby prolonging the activation of downstream signaling cascades (12), and in turn, enhancing growth factor-induced biologic functions.…”