Integrins are transmembrane receptors that help cell–cell and cell–extracellular matrix (ECM) adhesion. Upon ligand binding,integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle,organization of the intracellular cytoskeleton,and movement of new receptors to the cell membrane. The presence of integrins allows rapid and flexible responses to events at the cell surface.
Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collagen,fibrin,and heparan sulfate proteoglycans.
Coagulation,also known as clotting,is the process by which blood changes from a liquid to a gel,forming a blood clot. It results in hemostasis,the cessation of blood loss from a damaged vessel,followed by repair. The process of coagulation involves activation,adhesion and aggregation of platelets,as well as deposition and maturation of fibrin.
Von Willebrand factor (VWF) is a blood glycoprotein that promotes hemostasis,specifically,platelet adhesion. It is deficient and/or defective in von Willebrand disease and is involved in many other diseases,including thrombotic thrombocytopenic purpura,Heyde's syndrome,and possibly hemolytic–uremic syndrome. Increased plasma levels in many cardiovascular,neoplastic,metabolic,and connective tissue diseases are presumed to arise from adverse changes to the endothelium,and may predict an increased risk of thrombosis.
Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM),in a process called cell adhesion. In essence,CAMs help cells stick to each other and to their surroundings. CAMs are crucial components in maintaining tissue structure and function. In fully developed animals,these molecules play an integral role in generating force and movement and consequently ensuring that organs are able to execute their functions normally. In addition to serving as "molecular glue",CAMs play important roles in the cellular mechanisms of growth,contact inhibition,and apoptosis. Aberrant expression of CAMs may result in a wide range of pathologies,ranging from frostbite to cancer.
Disintegrins are a family of small proteins from viper venoms that function as potent inhibitors of both platelet aggregation and integrin-dependent cell adhesion.
Vitronectin is a glycoprotein of the hemopexin family which is synthesized and excreted by the liver,and abundantly found in serum,the extracellular matrix and bone. In humans it is encoded by the VTN gene.
Integrin beta-3 (β3) or CD61 is a protein that in humans is encoded by the ITGB3 gene. CD61 is a cluster of differentiation found on thrombocytes.
CD9 is a gene encoding a protein that is a member of the transmembrane 4 superfamily also known as the tetraspanin family. It is a cell surface glycoprotein that consists of four transmembrane regions and has two extracellular loops that contain disulfide bonds which are conserved throughout the tetraspanin family. Also containing distinct palmitoylation sites that allows CD9 to interact with lipids and other proteins.
Integrin alpha-IIb is a protein that in humans is encoded by the ITGA2B gene. ITGA2B,also known as CD41,encodes integrin alpha chain 2b. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. Alpha chain 2b undergoes post-translational cleavage to yield disulfide-linked light and heavy chains that join with beta 3 to form a fibrinogen receptor expressed in platelets that plays a crucial role in coagulation. Mutations that interfere with this role result in thrombasthenia. At least 38 disease-causing mutations in this gene have been discovered. In addition to adhesion,integrins are known to participate in cell-surface mediated signalling.
Integrin alpha-V is a protein that in humans is encoded by the ITGAV gene.
Integrin alpha-5 is a protein that in humans is encoded by the ITGA5 gene.
Platelet membrane glycoproteins are surface glycoproteins found on platelets (thrombocytes) which play a key role in hemostasis. When the blood vessel wall is damaged,platelet membrane glycoproteins interact with the extracellular matrix.
CD47 also known as integrin associated protein (IAP) is a transmembrane protein that in humans is encoded by the CD47 gene. CD47 belongs to the immunoglobulin superfamily and partners with membrane integrins and also binds the ligands thrombospondin-1 (TSP-1) and signal-regulatory protein alpha (SIRPα). CD-47 acts as a don't eat me signal to macrophages of the immune system which has made it a potential therapeutic target in some cancers,and more recently,for the treatment of pulmonary fibrosis.
Arginylglycylaspartic acid (RGD) is the most common peptide motif responsible for cell adhesion to the extracellular matrix (ECM),found in species ranging from Drosophila to humans. Cell adhesion proteins called integrins recognize and bind to this sequence,which is found within many matrix proteins,including fibronectin,fibrinogen,vitronectin,osteopontin,and several other adhesive extracellular matrix proteins. The discovery of RGD and elucidation of how RGD binds to integrins has led to the development of a number of drugs and diagnostics,while the peptide itself is used ubiquitously in bioengineering. Depending on the application and the integrin targeted,RGD can be chemically modified or replaced by a similar peptide which promotes cell adhesion.
A catch bond is a type of noncovalent bond whose dissociation lifetime increases with tensile force applied to the bond. Normally,bond lifetimes are expected to diminish with force. In the case of catch bonds,the lifetime of the bond actually increases up to a maximum before it decreases like in a normal bond. Catch bonds work in a way that is conceptually similar to that of a Chinese finger trap. While catch bonds are strengthened by an increase in force,the force increase is not necessary for the bond to work. Catch bonds were suspected for many years to play a role in the rolling of leukocytes,being strong enough to roll in presence of high forces caused by high shear stresses,while avoiding getting stuck in capillaries where the fluid flow,and therefore shear stress,is low. The existence of catch bonds was debated for many years until strong evidence of their existence was found in bacteria. Definite proof of their existence came shortly thereafter in leukocytes.
Fermitin family homolog 3) (FERMT3),also known as kindlin-3 (KIND3),MIG2-like protein (MIG2B),or unc-112-related protein 2 (URP2) is a protein that in humans is encoded by the FERMT3 gene. The kindlin family of proteins,member of the B4.1 superfamily,comprises three conserved protein homologues,kindlin 1,2,and 3. They each contain a bipartite FERM domain comprising four subdomains F0,F1,F2,and F3 that show homology with the FERM head (H) domain of the cytoskeletal Talin protein. Kindlins have been linked to Kindler syndrome,leukocyte adhesion deficiency,cancer and other acquired human diseases. They are essential in the organisation of focal adhesions that mediate cell-extracellular matrix junctions and are involved in other cellular compartments that control cell-cell contacts and nucleus functioning. Therefore,they are responsible for cell to cell crosstalk via cell-cell contacts and integrin mediated cell adhesion through focal adhesion proteins and as specialised adhesion structures of hematopoietic cells they are also present in podosome's F actin surrounding ring structure. Isoform 2 may act as a repressor of NF-kappa-B and apoptosis
The GPIb-IX-V complex is a profuse membrane receptor complex originating in megakaryocytes and exclusively functional on the surface of platelets. It primarily functions to mediate the first critical step in platelet adhesion,by facilitating binding to von Willebrand factor (VWF) on damaged sub-endothelium under conditions of high fluid shear stress. Although the primary ligand for the GPIb-V-IX receptor is VWF,it can also bind to a number of other ligands in the circulation such as thrombin,P-selectin,factor XI,factor XII,high molecular weight kininogen as well as bacteria. GPIb-IX-V offers a critical role in thrombosis,metastasis,and the life cycle of platelets,and is implicated in a number of thrombotic pathological processes such as stroke or myocardial infarction.
Nancy Hogg FMedSci is an immunologist who has made major contributions in the field of adhesion molecules,focusing on the integrins expressed by leukocytes. Hogg was elected to the Academy of Medical Sciences in 2002 and currently holds an emeritus position at the Francis Crick Institute,London.
