Integrin alpha 2
Integrin alpha-2, or CD49b (cluster of differentiation 49b), is a transmembrane protein which in humans is encoded by the CD49b gene.
The CD49b protein is an integrin alpha subunit. It makes up half of the α2β1 integrin duplex. Integrins are heterodimeric integral membrane glycoproteins composed of a distinct alpha chain and a common beta chain. They are found on a wide variety of cell types including T cells (the NKT cells), NK cells, fibroblasts and platelets. Integrins are involved in cell adhesion and also participate in cell-surface-mediated signalling. The α2β1 integrin functions primarily as a recepter for collagen, making it important in tissues like the skin, bone, and blood vessels.[5]
Expression of CD49b in conjunction with LAG-3 has been used to identify type 1 regulatory (Tr1) cells.[6]
The DX5 monoclonal antibody recognizes mouse CD49b.[7]
Interactions
[edit]Structure
[edit]The ITGA2 gene is located on chromosome 5q11.2 and encodes the integrin alpha-2 (CD49b) protein. This is a type I transmembrane Glycoprotein that belongs to the integrin alpha chain family.[10] The mature α2 subunit associates non-covalently with the β1 integrin subunit to form the α2β1 integrin receptor. This is a major collagen-binding integrin in vertebrates.[11]
Integrin α2 is an integrin alpha subunit, so it is made of a large extracellular domain, a single transmembrane domain, and a short cytoplasmic tail.[12][13] The extracellular region contains an inserted (I) domain, or the αI domain. This is responsible for recognizing and binding collagen molecules within the extracellular matrix.[12] Binding to collagen needs divalent cations such as magnesium (Mg2+) and manganese (Mn2+). This stabilizes the ligand-binding site and regulates receptor affinity.[11]
The α2β1 integrin has inactive and active conformations with different affinity for extracellular ligand. Intracellular signaling may lead to conformational changes of the integrin and increase the affinity to ligands (inside-out signaling), whereas ligand binding initiates signaling pathways that influence cell adhesion, migration, proliferation, and survival (outside-in signaling).[14]
Ligands
[edit]The main ligand for α2β1 integrin is collagen, and thus, it is considered one of the main receptors for collagen on mammalian cells.[15] The receptor interacts highly with fibrillar collagen types, especially type I collagen, which is plentiful in connective tissues including skin, tendon, and bone. It also recognizes type IV collagen, which is an important part of basement membranes and permits cells to associate with different ECM components.[12][13] Even though collagen is its primary ligand, there are several other proteins with which α2β1 integrin interacts, such as Laminin; however, the affinity in these cases is usually lower.[11]
The ligand binding occurs due to the presence of the inserted αI (I) domain that is located in the extracellular domain of the α2 subunit. The MIDAS domain of the protein binds divalent cation, magnesium ions (Mg²⁺) and manganese ions (Mn²⁺), required for the ligand binding.[14] Changes in conformation control the binding affinity of the receptor towards the extracellular ligands and help α2β1 integrin to change from an inactive to an active state under the influence of both extracellular and intracellular stimuli.[14]
The interaction between α2β1 integrin and collagen anchors cells to the extracellular matrix and initiates intracellular signaling pathways that regulate cellular behavior.[12][13]
Biological functions
[edit]Besides being a structural receptor, integrin α2β1 is a signaling receptor which receives signals from the extracellular medium to the intracellular part of the cell.[5]
Integrin α2β1 controls the process of cell migration. The process of cell migration takes place during embryogenesis, wound healing, and tissue remodeling. In these cases, the cells have to move through the extracellular matrix in a controlled manner. The interaction between α2β1 integrin and collagen functions in the migration of cells by creating focal adhesion that are specialized protein structures which assist in connecting actin filament of the cytoskeleton to the extracellular matrix.[8][13]
The receptor has a role in intracellular signaling pathway that regulate cell proliferation, cellular differentiation, and survival. It activates the signal molecules such as FAK, Src family of kinases, phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK). All these processes contribute to gene expression, reorganization of the cytoskeleton, and response to environmental cues.[14] These functions allow α2β1 in the regulation of normal tissue homeostasis and repair and adaptation of the cells to the changes in the environment provided by the extracellular matrix.[11] Integrin α2β1 is involved in the process of hemostasis as the integrin facilitates the adhesion of platelets to exposed collagen at sites of vascular damage.[16]
The receptor is also important to the immune system functioning. CD49b receptor is located on Natural killer cells, Natural killer T cells, and certain types of activated T cell. It mediates migration and cell-to-cell interactions within tissue microenvironments.[11] As for the use of the receptor in immunology, the co-expression of the CD49b receptor with the lymphocyte activation gene 3 receptor (LAG-3) is widely used in studies as a phenotypic marker of Tr1 regulatory T cell, which is a particular type of regulatory T cell responsible for maintaining immune tolerance.[6]
Not only in physiological conditions, but also in the case of pathologies, the integrin α2β1 participates in tissue remodeling and turnover of extracellular matrix. The pathway of collagen signal transduction through the integrin α2β1 controls collagen production and other aspects of matrix organization.[15] The pathology in case of disorders of this process may be observed in fibrosis, whereas dysregulation of α2β1 integrin expression is linked to metastasis and tumor invasion. It may be concluded that integrin α2β1 is a functional molecule, and not only a molecular structure for adhesion.[9][12]
Immune function
[edit]
Hemostasis is a natural mechanism for minimizing blood loss due to vessel damage while ensuring adequate blood circulation in the organism under Physiologically normal conditions. Platelet adhesion to the exposed collagen due to the action of integrin α2β1 is one of the mechanisms of primary hemostasis. In the state of physiological health, collagen is present below the endothelium and is not accessible to platelets circulating in the blood stream. The damage to the walls of the vessel makes collagen accessible for the platelets and allows them to adhere to collagen fibers due to the activity of platelet collagen receptors, such as α2β1 integrin and GPVI.[16]
In contrast to the GPVI functioning as a signaling receptor, α2β1 mainly provides the stabilization of the platelet adhesion to the collagen and facilitates their stable fixation on the damaged area.[15] This process is especially necessary in case of high shear stresses in the arteries due to the negative impact of the blood flow force on platelets' fixation. The enhanced adhesion allows attracting more platelets and forming a stable thrombus that is capable of minimizing blood loss.[16]
α2β1-mediated collagen binding also stimulates outside-in signaling, which plays a role in platelet spreading and cytoskeletal remodeling, thus increasing the surface area of the activated platelets and providing a way for interaction between them and neighboring platelets and coagulation factors. This process helps in the stabilization of the forming clot.[14] Though α2β1 receptor on its own cannot activate the platelets completely, it cooperates with other platelet receptors such as GPVI, to form a thrombus after vascular injury.[16]
The α2β1 integrin facilitates primary hemostasis through platelet adhesion to collagen exposed after injury to the Endothelial cells of blood vessels. In healthy vessels, collagen is found underneath the endothelial cells and is not accessible to platelets flowing through the blood vessels. After wounding, the collagen is exposed and enables the platelet receptors for collagen, such as α2β1 integrin and GPVI, to adhere to the wound surface and begin the formation of a hemostatic plug.[16] Unlike GPVI, that is mainly responsible for signal transduction, α2β1 integrin is predominantly responsible for increasing platelet adhesion to collagen and stabilizing platelet attachment to the site of injury.[15]
Stable engagement becomes especially relevant in situations involving high shear stress in the arterial system because the force of the flowing blood might disrupt the attachment of platelets. Through strengthening adhesion, α2β1 integrin facilitates aggregation of extra platelets and the development of a stable thrombus that is capable of stopping the bleeding.[16] The engagement of collagen receptors through α2β1 integrin stimulates inside-out signaling and platelet spreading as well as remodeling of the cytoskeleton. This results in increased surface area of platelets, making their contact with surrounding platelets and coagulation factors possible.[14]
Platelet adhesion being important for physiological hemostasis, any variations in the expression of ITGA2 gene or its products may affect the rate of bleeding or development of thrombosis. There are some polymorphism of the ITGA2 gene, the presence of which results in various collagen-binding capacities in people due to different densities of the α2β1 receptor on the platelets' surface.[17] Though the impact of these variations is still unclear, their relation to myocardial infarction and Ischemic stroke has been studied. Therefore, α2β1 receptor still remains an interesting Therapeutic target for the prevention of pathological thrombosis.[18]
Clinical significance
[edit]Deregulation of the expression and function of ITGA2 has been shown to be involved in a number of pathological states such as cancer, fibrosis, and cardiovascular disease. As integrin α2β1 mediates cellular interactions with the extracellular matrix, any changes in its expression may affect cellular activity and disease development.[14]
One of the most studied functions of the α2β1 integrin is connected with cancer biology. It has been shown that dysregulated expression of ITGA2 occurs in a number of cancers including breast, prostate, pancreatic, lung, colorectal, and gastric cancer.[19] In most types of tumors, elevated expression of α2β1 increases the capacity of cancer cells to bind with collagen-rich extracellular matrices and migrate to other tissues. However, there is evidence that in some cancers the function of α2β1 might be involved in tumor suppression due to the maintenance of normal cell-matrix interactions.[12]
Further, changes in the level of activity of α2β1 have been associated with development of fibrosis. This condition is known to be associated with the deposition of excess quantities of extracellular matrix components, mostly collagens. Therefore, the activation of the signaling pathways mediated by the α2β1 integrin is likely to play a role in matrix remodeling in conditions such as pulmonary, hepatic, renal, and cardiac fibrosis.[12] As a result, scientists have hypothesized that it might be possible to regulate the activity of α2β1 to prevent collagen accumulation.
As for Thrombotic disease, there have been several attempts to identify the contribution of α2β1-related genes to the development of this disorder. For example, polymorphisms in the ITGA2 gene can influence the density of α2β1 receptors in the platelet membrane, thus affecting the interaction of platelets with collagen and, consequently, their ability to form thrombi.[17] However, the relationship of the described polymorphisms to myocardial infarction or ischemic stroke was rather inconsistent.[17][18]
It has also been reported that ITGA2 can be used as a biomarker for the diagnosisand prognosis of diseases. Overexpression of the ITGA2 gene is correlated with worse outcomes of several types of cancers, which implies the possibility of predicting aggressiveness, metastasis and survival based on the expression of this protein.[19] With further development of transcriptomics and proteomics studies, ITGA2 was recognized as one of the candidates for a biomarker of disease progression and evaluation of the effect of targeted therapies.[19]
Since this integrin is responsible for many pathologies, it has become an attractive target for therapy. Monoclonal antibodies, peptides, and other molecules were developed to inhibit the functions of integrin α2β1 related to binding of cells to extracellular matrix components and subsequent signal transduction. However, there are no specific therapeutic agents targeting integrin α2β1 currently available for clinical use.[12][19]
References
[edit]- 1 2 3 GRCh38: Ensembl release 89: ENSG00000164171 – Ensembl, May 2017
- 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000015533 – Ensembl, May 2017
- ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- 1 2 "Entrez Gene: ITGA2 integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor)".
- 1 2 Gagliani N, Magnani CF, Huber S, Gianolini ME, Pala M, Licona-Limon P, et al. (June 2013). "Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells". Nature Medicine. 19 (6): 739–746. doi:10.1038/nm.3179. PMID 23624599. S2CID 21305032.
- ↑ Arase H, Saito T, Phillips JH, Lanier LL (August 2001). "Cutting edge: the mouse NK cell-associated antigen recognized by DX5 monoclonal antibody is CD49b (alpha 2 integrin, very late antigen-2)". Journal of Immunology. 167 (3). Baltimore: 1141–1144. doi:10.4049/jimmunol.167.3.1141. PMID 11466327.
- 1 2 Stricker TP, Dumin JA, Dickeson SK, Chung L, Nagase H, Parks WC, et al. (August 2001). "Structural analysis of the alpha(2) integrin I domain/procollagenase-1 (matrix metalloproteinase-1) interaction". The Journal of Biological Chemistry. 276 (31): 29375–29381. doi:10.1074/jbc.M102217200. PMID 11359774.
- 1 2 Dumin JA, Dickeson SK, Stricker TP, Bhattacharyya-Pakrasi M, Roby JD, Santoro SA, et al. (August 2001). "Pro-collagenase-1 (matrix metalloproteinase-1) binds the alpha(2)beta(1) integrin upon release from keratinocytes migrating on type I collagen". The Journal of Biological Chemistry. 276 (31): 29368–29374. doi:10.1074/jbc.M104179200. PMID 11359786.
- ↑ "ITGA2 integrin subunit alpha 2 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2026-07-23.
- 1 2 3 4 5 "UniProt". UniProt. Retrieved 2026-07-23.
- 1 2 3 4 5 6 7 8 Heino J (2014), "Cellular Signaling by Collagen-Binding Integrins", in Gullberg D (ed.), I Domain Integrins, Dordrecht: Springer Netherlands, pp. 143–155, doi:10.1007/978-94-017-9153-3_10, ISBN 978-94-017-9153-3, retrieved 2026-07-23
- 1 2 3 4 White DJ, Puranen S, Johnson MS, Heino J (August 2004). "The collagen receptor subfamily of the integrins". The International Journal of Biochemistry & Cell Biology. 36 (8): 1405–1410. doi:10.1016/j.biocel.2003.08.016. PMID 15147720.
- 1 2 3 4 5 6 7 Hynes RO (September 2002). "Integrins". Cell. 110 (6): 673–687. doi:10.1016/s0092-8674(02)00971-6. ISSN 0092-8674.
- 1 2 3 4 Heino J (August 2000). "The collagen receptor integrins have distinct ligand recognition and signaling functions". Matrix Biology. On the occasion of the XVII Meeting of the FECTS. 19 (4): 319–323. doi:10.1016/S0945-053X(00)00076-7. PMID 10963992.
- 1 2 3 4 5 6 Nieswandt B, Watson SP (July 2003). "Platelet-collagen interaction: is GPVI the central receptor?". Blood. 102 (2): 449–461. doi:10.1182/blood-2002-12-3882. PMID 12649139.
- 1 2 3 Kunicki TJ, Kritzik M, Annis DS, Nugent DJ (March 1997). "Hereditary variation in platelet integrin alpha 2 beta 1 density is associated with two silent polymorphisms in the alpha 2 gene coding sequence". Blood. 89 (6): 1939–1943. PMID 9058714.
- 1 2 Kunicki TJ (January 2002). "The influence of platelet collagen receptor polymorphisms in hemostasis and thrombotic disease". Arteriosclerosis, Thrombosis, and Vascular Biology. 22 (1): 14–20. doi:10.1161/hq0102.100458. PMID 11788455.
- 1 2 3 4 Cooper J, Giancotti FG (March 2019). "Integrin Signaling in Cancer: Mechanotransduction, Stemness, Epithelial Plasticity, and Therapeutic Resistance". Cancer Cell. 35 (3): 347–367. doi:10.1016/j.ccell.2019.01.007. PMC 6684107. PMID 30889378.
Further reading
[edit]- Moroi M, Jung SM (July 1997). "Platelet receptors for collagen". Thrombosis and Haemostasis. 78 (1): 439–444. doi:10.1055/s-0038-1657566. PMID 9198193. S2CID 8121197.
- Takada Y, Kamata T, Irie A, Puzon-McLaughlin W, Zhang XP (October 1997). "Structural basis of integrin-mediated signal transduction". Matrix Biology. 16 (4): 143–151. doi:10.1016/S0945-053X(97)90002-0. PMID 9402003.
- Dickeson SK, Santoro SA (June 1998). "Ligand recognition by the I domain-containing integrins". Cellular and Molecular Life Sciences. 54 (6): 556–566. doi:10.1007/s000180050184. PMC 11147323. PMID 9676575. S2CID 9775686.
- Porter JC, Hogg N (October 1998). "Integrins take partners: cross-talk between integrins and other membrane receptors". Trends in Cell Biology. 8 (10): 390–396. doi:10.1016/S0962-8924(98)01344-0. PMID 9789327.
- Plenz GA, Deng MC, Robenek H, Völker W (January 2003). "Vascular collagens: spotlight on the role of type VIII collagen in atherogenesis". Atherosclerosis. 166 (1): 1–11. doi:10.1016/S0021-9150(01)00766-3. PMID 12482545.
- Charakida M, Tousoulis D, Stefanadis C, Toutouzas P (January 2003). "The impact of platelet glycoprotein IIIa and Ia polymorphisms in cardiovascular thrombotic disease". Italian Heart Journal. 4 (1): 17–22. PMID 12690916.
- Tsantes AE, Nikolopoulos GK, Bagos PG, Vaiopoulos G, Travlou A (May 2007). "Lack of association between the platelet glycoprotein Ia C807T gene polymorphism and coronary artery disease: a meta-analysis". International Journal of Cardiology. 118 (2): 189–196. doi:10.1016/j.ijcard.2006.06.047. PMID 17023078.
External links
[edit]- CD49b+antigen at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- PDBe-KB provides an overview of all the structure information available in the PDB for Human Integrin alpha 2
- "ITGA2". Cell Migration Gateway.
{{cite web}}: CS1 maint: deprecated archival service (link) - Human ITGA2 genome location and ITGA2 gene details page in the UCSC Genome Browser.
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