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Vitronectin

Vitronectin is a multifunctional adhesive glycoprotein primarily synthesized in the liver and present in human blood plasma at concentrations of 200–400 μg/mL, as well as in the extracellular matrix of various tissues including the heart, brain, and skeletal muscle.^[1]^[2] It exists as a single-chain monomer in plasma or as multimers in the extracellular matrix, featuring key structural domains such as the heparin-binding region, a Somatomedin B domain, and an RGD (Arg-Gly-Asp) sequence that facilitates interactions with integrins.^[1]^[2] This protein promotes cell adhesion and migration by binding to integrins such as αvβ3 and αvβ5, thereby linking cells to the extracellular matrix and supporting processes such as wound healing and tissue remodeling.^[1]^[2] Vitronectin also regulates coagulation and fibrinolysis through its interaction with plasminogen activator inhibitor-1 (PAI-1), stabilizing it to inhibit plasmin formation and modulate thrombin activity, while its multimeric form in tissues aids in matrix stabilization.^[1]^[2] Additionally, it inhibits the complement system by binding to the terminal complement complex, preventing membrane attack, and exhibits antimicrobial properties that contribute to innate immunity.^[1] Beyond these roles, vitronectin influences pathological processes including tumorigenesis, where it enhances tumor cell adhesion, migration, and metastasis via integrin-mediated signaling, and is implicated in neurodegenerative conditions through its interactions at the blood-brain barrier.^[1]^[3] Encoded by the VTN gene on chromosome 17q11.2, vitronectin is highly expressed in hepatic tissue and interacts with diverse partners such as urokinase plasminogen activator receptor (uPAR), collagen, and heparin, underscoring its versatility in both physiological and disease contexts.^[1]^[2]

Discovery and Biosynthesis

Historical Discovery

Vitronectin was first identified in 1967 by Robert Holmes as a "serum spreading factor," a protein fraction from human serum that promotes the attachment and spreading of unadapted cells on glass surfaces, enabling their immediate growth in vitro. Early research also recognized the protein under alternative names reflecting its diverse activities: "epibolin," identified in 1981 for its role in supporting epithelial cell movement and migration, and "S protein," noted in the 1970s for its ability to inhibit the terminal complement pathway by binding to the C5b-7 complex. During the 1970s, studies confirmed its presence in human serum and the extracellular matrix, with binding experiments demonstrating its adhesion to plastic surfaces and facilitation of cell spreading, as shown through partial purification and functional assays. A major milestone occurred in 1985 when Suzuki et al. deduced the complete amino acid sequence of human vitronectin from cDNA, revealing a 478-residue precursor polypeptide and highlighting similarities in cell attachment sites with fibronectin. In the 1980s, the protein was formally renamed vitronectin based on its Latin roots ("vita" for life and "nectere" for to bind), and sequence analysis established its membership in the hemopexin family due to shared structural domains.

Gene Expression and Protein Synthesis

Vitronectin is encoded by the VTN gene, located on the long arm of human chromosome 17 at position 17q11.2, spanning approximately 5.8 kb and consisting of eight exons.^[1] ^[3] The gene produces multiple transcripts through alternative splicing, with the canonical transcript encoding a precursor protein of 478 amino acids, including a 19-amino-acid signal peptide that directs it to the secretory pathway.^[4] ^[1] Expression of VTN is predominantly restricted to the liver, where it is synthesized by hepatocytes and secreted into the plasma as a soluble glycoprotein.^[5] Minor levels of expression occur in other tissues, including the spleen and placenta, though these contribute negligibly to circulating levels.^[5] ^[6] Transcriptional regulation of VTN is governed by liver-enriched factors that ensure its hepatocyte-specific production, maintaining plasma concentrations of approximately 200–400 μg/mL in healthy adults.^[7] ^[2] Biosynthesis begins with translation of the pre-pro-vitronectin precursor, followed by cleavage of the N-terminal signal peptide in the endoplasmic reticulum, yielding a mature 459-amino-acid monomer with an apparent molecular mass of 75 kDa due to glycosylation.^[4] ^[8] This single-chain form predominates in plasma. In extracellular matrix contexts, proteolytic processing at the Arg379-Ala380 bond generates a two-chain isoform, where the N-terminal (65 kDa) and C-terminal (10 kDa) fragments remain covalently linked by disulfide bonds, altering its conformation and localization.^[9] ^[10]

Molecular Structure

Primary Sequence and Domains

The mature form of human vitronectin comprises 459 amino acid residues following cleavage of the 19-residue signal peptide, with an approximate 50% hydrophilic composition that contributes to its solubility and functionality in serum.^[11] This sequence includes the tripeptide Arg-Gly-Asp (RGD) motif at residues 45–47, which constitutes the core recognition site for integrin-mediated interactions.^[12] Vitronectin exhibits a modular architecture defined by several principal domains. The N-terminal Somatomedin B-like domain (residues 1–44) is stabilized by four intramolecular disulfide bonds formed from eight cysteine residues. The central region (residues 45–379) is flexible and proline-rich, containing the RGD motif, heparin-binding sites essential for glycosaminoglycan interactions (e.g., residues 82–137), and two hemopexin-like domains (HX1: residues 53–128; HX2: residues 144–247) that fold into compact beta-propeller subdomains resembling hemopexin repeats, enabling collagen binding and contributing to overall structural integrity. Plasminogen activator inhibitor-1 (PAI-1) binding primarily occurs via the Somatomedin B domain. The C-terminal tail (residues 380–459, post-cleavage) aids in multimerization and additional matrix interactions.^[13]^[14] High-resolution structural insights are available for isolated domains but not the intact protein. The N-terminal Somatomedin B-like domain has been elucidated by X-ray crystallography (PDB: 1S4G) and nuclear magnetic resonance spectroscopy (PDB: 1SSU), revealing a compact cystine-knot fold with exposed loops for ligand engagement. As of 2025, the full-length vitronectin lacks a crystal or cryo-EM structure, relying instead on homology models and computational predictions such as AlphaFold for overall architecture.^[15] In physiological contexts, vitronectin circulates as a monomer in plasma, maintaining a compact, low-activity conformation, but undergoes conformational activation to form high-molecular-weight multimers upon incorporation into the extracellular matrix, thereby enhancing matrix assembly and stability.^[16]

Post-Translational Modifications

Vitronectin undergoes several post-translational modifications that influence its structural stability, localization within the extracellular matrix (ECM), and functional activity. These modifications include glycosylation, proteolytic processing, phosphorylation, sulfation, and cross-linking events that promote multimerization. Glycosylation is a prominent modification, accounting for approximately 15-20% of vitronectin's molecular weight. The protein features four N-linked glycosylation sites at asparagine residues 47, 106, 211, and 310, where complex glycan chains with sialic acid termini are attached, contributing to its solubility and protection from proteolysis. Additionally, O-linked glycosylation occurs at serine and threonine residues within Ser/Thr-rich regions, further modulating the protein's conformation and interactions with ECM components. These glycan structures are primarily hybrid and biantennary complex types, with variations in sialylation and fucosylation observed across physiological states.^[17]^[18] Proteolytic processing of vitronectin occurs post-secretion, involving cleavage at the Arg379-Ala380 bond by an unidentified protease. This generates a two-chain form consisting of a 65 kDa N-terminal chain and a 10 kDa C-terminal chain, which remain covalently linked via a disulfide bond between Cys385 and Cys447. The single-chain 75 kDa form predominates in plasma, while the processed form is more abundant in tissues, potentially enhancing its incorporation into the ECM. This cleavage is influenced by a polymorphism at position 381 (methionine or threonine), which correlates with susceptibility to proteolysis.^[19]^[20] Phosphorylation and sulfation sites are concentrated in the N-terminal Somatomedin B (SMB) domain (residues 1-44), where they regulate responsiveness to thrombin. Casein kinase II phosphorylates threonines 50 and 57, while protein kinase C targets serine 362, and protein kinase A modifies serine 378; these modifications occur extracellularly and may alter heparin-binding affinity. Tyrosine sulfation at positions 56 and 59 in the SMB domain is stoichiometric at Tyr56 and partial at Tyr59, enhancing interactions with thrombin-antithrombin complexes and promoting localized activation in hemostatic processes.^[21]^[22]^[23] In the ECM, vitronectin undergoes conformational changes leading to multimerization through transglutaminase-mediated cross-linking, primarily via glutamine and lysine residues in the heparin-binding domain. This process converts soluble monomers into insoluble multimers, stabilizing the protein in fibrillar structures and reducing its solubility for prolonged matrix retention. Such multimers exhibit enhanced adhesive properties compared to monomeric forms.^[16]^[24]

Physiological Functions

Cell Adhesion and Migration

Vitronectin plays a central role in cell adhesion by binding to specific integrins on the cell surface, primarily through its Arg-Gly-Asp (RGD) motif located in the central domain of the protein. This motif facilitates interactions with αvβ3 and αvβ5 integrins, which are expressed on various cell types including endothelial cells and fibroblasts, enabling attachment to extracellular matrix substrates. Additionally, vitronectin binds to αIIbβ3 integrins on platelets, supporting adhesion in dynamic environments. These interactions are critical for initiating cellular responses to the extracellular matrix, as demonstrated in studies showing that RGD-mediated binding promotes stable anchorage without triggering excessive signaling cascades.^[25] Through these integrin engagements, vitronectin promotes the spreading and migration of key cell populations involved in tissue repair, such as fibroblasts, endothelial cells, and smooth muscle cells. For instance, endothelial cell spreading on vitronectin-coated surfaces triggers intracellular calcium elevation and cytoskeletal reorganization, facilitating extension of lamellipodia and enhanced motility essential for angiogenesis. In fibroblasts and smooth muscle cells, vitronectin supports focal adhesion formation and stabilization, allowing cells to exert traction forces on the substrate and advance during wound healing processes. This is evidenced by in vitro assays where vitronectin substrates significantly increase cell spreading rates compared to non-adhesive controls, underscoring its role in maintaining cell-matrix connectivity.^[26]^[27]^[28] Vitronectin further enhances cell migration by interacting with the urokinase plasminogen activator receptor (uPAR), which directs pericellular proteolysis at the leading edge of migrating cells. This uPAR-vitronectin complex stabilizes focal adhesions and modulates integrin signaling, promoting directed movement without reliance on direct matrix degradation. The interaction requires the non-RGD heparin-binding domain of vitronectin and uPAR's somatomedin B-like domain, leading to activation of downstream pathways like focal adhesion kinase that regulate actin dynamics. In vivo, vitronectin deficiency in knockout mice results in delayed wound closure and impaired microvascular angiogenesis, with reduced vessel sprouting observed between days 7 and 14 post-injury, highlighting its physiological necessity for coordinated cellular migration in tissue repair.^[29]^[30]^[31]

Hemostasis and Fibrinolysis

Vitronectin plays a crucial role in maintaining the balance between hemostasis and fibrinolysis by modulating key proteolytic processes during blood clot formation and resolution. Through its interactions with components of the coagulation and fibrinolytic systems, vitronectin helps prevent excessive bleeding while inhibiting untimely clot breakdown, thereby supporting vascular integrity.^[32] A primary mechanism involves the high-affinity binding of vitronectin to plasminogen activator inhibitor-1 (PAI-1), with a dissociation constant (Kd) of approximately 0.1–1 nM, occurring primarily through its N-terminal somatomedin B domain. This interaction stabilizes the active conformation of PAI-1, extending its functional lifetime and enhancing its ability to inhibit tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA), thereby suppressing premature fibrinolysis and promoting clot stability. By localizing PAI-1 to the fibrin clot surface via vitronectin's incorporation into the extracellular matrix (ECM), this binding further concentrates inhibitory activity at sites of injury, fine-tuning the proteolytic environment to favor hemostasis over lysis.^[33]^[34] Vitronectin also facilitates platelet aggregation and thrombus formation by interacting with the integrin αIIbβ3 on platelet surfaces, serving as a ligand that supports platelet adhesion and spreading within developing thrombi. This binding promotes the recruitment and stabilization of platelets at vascular injury sites, contributing to the structural integrity of the clot. Additionally, vitronectin localizes to thrombi through its incorporation into fibrin networks during coagulation, enhancing overall thrombus cohesion.^[35] The heparin-binding domain of vitronectin further regulates thrombin activity by competing for heparin binding, thereby modulating thrombin's interaction with antithrombin III and influencing fibrin formation. This competition limits excessive thrombin generation while allowing controlled fibrin polymerization, which aids in clot stabilization without promoting uncontrolled proteolysis. Overall, these multifaceted actions position vitronectin as a key regulator that inhibits hyperfibrinolysis and supports ECM-associated clot maintenance, ensuring physiological hemostatic balance.^[36]

Complement Regulation

Vitronectin serves as a key regulator of the terminal complement pathway by binding to the nascent terminal complement complex (TCC), particularly forming a stable SC5b-7 complex that occupies the metastable membrane-binding site of C5b-7 and prevents the assembly and insertion of the membrane attack complex (MAC) into host cell membranes.^[37] This interaction inhibits the lytic potential of the complement system, protecting bystander cells from unintended damage during immune activation.^[38] The binding site for C5b-7 on vitronectin is localized to a 43-kDa internal domain, distinct from other regulatory regions of the protein.^[39] Historically referred to as S-protein, vitronectin earned this name from its function as a soluble inhibitor of complement-mediated lysis; it additionally binds to C9, restricting its polymerization and thereby disrupting the formation of the pore-like MAC structure essential for cell lysis.^[38] This dual mechanism—primarily through SC5b-7 stabilization and secondarily via C9 inhibition—ensures effective control over the terminal pathway, with the C9-binding activity mediated by non-heparin domains within the protein.^[39] Unlike its primary action on early TCC intermediates, the effect on C9 is less pronounced but contributes to overall cytolysis prevention.^[37] The plasma form of vitronectin circulates at high concentrations (approximately 200-400 μg/mL) to suppress systemic complement activation and limit widespread tissue damage, while its incorporation into the extracellular matrix (ECM) during inflammation provides localized protection to endothelial and parenchymal cells.^[40] This ECM-bound variant maintains its inhibitory capacity, anchoring near sites of potential complement deposition to safeguard host tissues without interfering with pathogen targeting.^[41] In vitro haemolytic assays using guinea pig erythrocytes demonstrate that vitronectin and its proteolytic fragments (e.g., 53-kDa and 43-kDa) potently inhibit reactive lysis by blocking C5b-7 membrane attachment and C9 polymerization, achieving significant reductions in complement-mediated cell destruction.^[39] Studies in vitronectin-deficient mouse models reveal heightened susceptibility to injury, with exacerbated complement-driven damage in inflammatory contexts such as acute lung injury, underscoring its protective role against excessive TCC activity.^[42] Vitronectin also exhibits antimicrobial properties that contribute to innate immunity. It can directly inhibit bacterial growth by binding to bacterial adhesins and disrupting pathogen adhesion to host cells, while its complement-regulatory functions prevent excessive immune damage that could benefit pathogens. This dual role enhances host defense against infections.^[43]

Pathological Roles

Role in Cancer Progression

Vitronectin plays a critical role in promoting cancer metastasis by enhancing tumor cell adhesion and migration through its interaction with the integrin αvβ3. This binding facilitates the attachment of cancer cells to the extracellular matrix (ECM), enabling invasive behavior and dissemination to distant sites. In breast cancer, vitronectin upregulation is observed in tumor tissues and cell lines, where it drives metastasis via the PI3K/AKT signaling pathway activated by αvβ3 engagement.^[44] Similarly, in neuroblastoma, vitronectin is highly expressed in the tumor microenvironment, correlating with increased cell adhesion, migration, and aggressive metastatic potential.^[45] In lung cancer, vitronectin supports metastasis by mediating αvβ3-dependent adhesion and migration, contributing to the spread of tumor cells to secondary organs such as bone.^[46] Vitronectin also supports angiogenesis in the tumor microenvironment by being recruited to the ECM, where it stabilizes nascent blood vessels through integrin signaling. Its interaction with αvβ3 on endothelial cells activates pathways like VEGFR-2, promoting endothelial cell proliferation and vessel formation essential for tumor nutrient supply and growth.^[47] This angiogenic role is particularly evident in neuroblastoma, where vitronectin deposition in the ECM fosters a pro-vascular niche that sustains tumor expansion.^[47] Furthermore, vitronectin facilitates proteolytic events critical for cancer invasion by binding plasminogen activator inhibitor-1 (PAI-1), which modulates the urokinase-type plasminogen activator (uPA)/uPAR system. This interaction enables localized ECM degradation through plasmin generation, allowing tumor cells to breach basement membranes and invade surrounding tissues; vitronectin stabilizes uPAR on the cell surface, enhancing uPA-mediated proteolysis while PAI-1 regulates the process to prevent excessive degradation.^[48] In this context, vitronectin's brief association with uPAR further amplifies migratory signals during metastasis.^[48] Recent research highlights vitronectin's therapeutic vulnerability in high-risk neuroblastoma (HR-NB), where novel inhibitors targeting its binding affinity significantly reduce tumor cell viability by disrupting ECM interactions and signaling. These inhibitors show promise as targeted therapies, potentially improving outcomes in aggressive cases linked to vitronectin-driven ECM remodeling. As of August 2024, elevated plasma vitronectin levels have been identified as a prognostic biomarker in neuroblastoma patients, correlating with advanced stages, metastatic disease, and reduced progression-free survival; in 3D tumor models, vitronectin secretion further supports its role in tumor progression and resistance.^[49] Over-expression of vitronectin in gastric cancer tissues correlates with poor survival.^[50]

Involvement in Thrombosis and Vascular Disorders

Vitronectin plays a significant role in enhancing thrombosis through its incorporation into fibrin clots, where its multimeric form promotes platelet adhesion and aggregation via homotypic interactions between platelet-associated and fibrin-bound vitronectin.^[51] This stabilization of thrombi contributes to vessel occlusion, as demonstrated in murine models of arterial injury where vitronectin-deficient mice exhibit unstable thrombi, increased emboli formation, and delayed occlusion times compared to wild-type controls.^[52] By binding to platelet glycoproteins and integrins, vitronectin facilitates the second wave of platelet aggregation under low thrombin concentrations and high shear stress, underscoring its prothrombotic effects in pathological clotting.^[52] Additionally, vitronectin stabilizes plasminogen activator inhibitor-1 (PAI-1), thereby inhibiting fibrinolysis and further promoting vascular thrombosis in models of arterial and venous injury.^[53] In atherosclerosis, vitronectin accumulates within atherosclerotic plaques, particularly in the intima and media of affected arteries, where it is locally synthesized by smooth muscle cells (SMCs) and potentially derived from plasma or platelet release.^[54] This accumulation facilitates SMC proliferation and migration through interactions with integrins αvβ3 and αvβ5, contributing to intimal thickening and plaque progression.^[54] Vitronectin also regulates pericellular proteolysis and cell attachment in the vascular wall, exacerbating lipid accumulation, monocyte infiltration, and extracellular matrix remodeling characteristic of coronary atherosclerosis.^[55] Vitronectin levels are altered in aneurysmal and restenotic vascular disorders. In abdominal aortic aneurysms, vitronectin is present in the aneurysm wall and associated proteins, with proteomic analyses indicating its involvement in matrix remodeling, though decreased levels correlate with larger aneurysm diameters and higher rupture risk.^[56] For restenosis following coronary stenting, elevated vitronectin expression and plasma concentrations are observed in affected patients, predicting adverse outcomes such as neointimal hyperplasia; inhibitors targeting vitronectin-integrin interactions have shown potential to reduce this proliferation in preclinical models.^[57] Rare mutations in the VTN gene, including promoter variants, have been linked to vascular disorders, with vitronectin deficiency in murine models resulting in mild bleeding tendencies due to altered fibrinolytic balance and focal hemorrhage sites, alongside paradoxically increased thrombosis risk from unstable clot formation.^[58]^[31] Systemic vitronectin deficiency also attenuates aortic inflammation and atherosclerosis progression, highlighting its pathological overactivity in thrombotic conditions.^[59] Therapeutically, anti-vitronectin strategies, such as monoclonal antibodies targeting vitronectin-PAI-1 complexes or homotypic interactions, have been tested in animal models of arterial injury, demonstrating reduced platelet adhesion, thrombus stability, and neointimal hyperplasia without excessive bleeding, with preclinical data up to 2023 supporting their potential for thrombosis prevention.^[51]^[52]

References

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Vitronectin - an overview | ScienceDirect Topics
Vitronectin is a glycoprotein, mainly from the liver, that plays roles in wound healing, tissue remodeling, cell adhesion, and cell migration.
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