Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Integrin α2 (ITGA2)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_238


Historical Background

The integrin family of cellular receptors contains 24 α/β heterodimers that mediate adhesion to extracellular matrix (ECM), plasma proteins, or counter receptors on other cells. The cytoplasmic domains of integrin α and β subunits are linked to cytoskeleton and cellular signaling pathways. Integrin α2 subunit forms a heterodimer with integrin β1 subunit and acts as a cellular collagen receptor. Before this receptor was realized to be a member of the integrin family, the α2 subunit had already been named as the α subunit of T lymphocyte very late activation antigen 2 (VLA-2), platelet collagen receptor (glycoprotein Ia), and the larger subunit of collagen-binding extracellular matrix receptor II. Integrin α2β1 forms together with three other heterodimers, namely, α1β1, α10β1, and α11β1, the collagen receptor subfamily of the integrins (Hynes 2004).


Integrins are single-pass type I membrane glycoproteins. α2 belongs to a subgroup of integrins that contain an inserted domain (I domain that is often called as A domain, based on its structural similarity with von Willebrand factor A domain) (Fig. 1). Integrin αI domains recognize and bind ligands using a magnesium-containing metal ion-dependent coordination site (MIDAS). Integrin α2 subunit contains short intracellular domain, transmembrane anchor, and an extracellular part, composed of α2I, β-propeller, thigh, calf-1, and calf-2 domains. In α2–β1 complex, the β-propeller domain (α subunit) binds to β1I domain (β subunit) in a noncovalent manner. These two domains, together with the α2I domain, form the “head” part of the heterodimer. Thigh, calf-1, and calf-2 domains form the “leg” part of α2 subunit, while β1 leg is composed of hybrid, PSI, four I-EGF (1–4), and β-tail domains. The leg parts of integrins can be bended in “knees” between thigh and calf-1 domain (α subunit) or between hybrid and I-EGF-1 domain (β subunit) (Arnaout et al. 2007; Luo et al. 2007).
Integrin α2 (ITGA2), Fig. 1

Domain structure of integrin α2β1, a collagen receptor. αI (αA) domain is a high affinity binding site for fibril-forming collagen, but the receptor has been reported to bind numerous other ligands, as well. Ligand binding leads to signaling that regulates, for example, cell proliferation, differentiation, and survival

Evolution and Tissue Distribution in Human

Based on their structure and phylogeny, human integrin α subunits can be divided into four different subfamilies, namely, RGD-motif binding integrins, α4/α9 integrins, laminin binding integrins, and αI domain integrins. While all metazoans have integrins, integrin αI domains exist in Chordates only. Accordingly, the collagen receptor integrins, including α2β1, are not found in nonvertebrates. The evolutionary history of the collagen receptors is in accordance with the fact that their biological functions are often related to immunity and tissue regeneration (Johnson et al. 2009).

Integrin α2β1 is abundantly expressed in human tissues. This integrin is considered to predominantly be epithelial, but also fibroblasts, chondrocytes, osteoblasts, and endothelial cell are α2 positive. Integrin α2β1 is one of the collagen receptors on platelets. Activated T lymphocytes (e.g., Th17 cells), mast cells, and neutrophils express this receptor, as well (Eckes et al. 2006; Heino 2007; Johnson et al. 2009; Madamanchi et al. 2014; Zeltz and Gullberg 2016).


Distinct members of the collagen family are the major ligands for α2β1 integrin. In collagenous ligands, α2I domain interacts with special triple-helical motifs, containing amino acid sequences such as GFOGER (O = hydroxyproline), GLOGER, GASGER, GROGER, and GLOGEN. The collagen family contains 28 different members and many of them are only known at nucleic acid level, and therefore, it has not been possible to test them in binging assays with integrins. At least fibril-forming collagens (I, II, III, V, XI), basement-membrane collagen (IV), fibril-associated collagens with interruptions in triple-helix (FACITs, IX, XIV), network-forming collagens (VIII, X), beaded-filament forming collagens (VI), and anchoring filaments forming collagens (VII) are ligands for α2β1. Collagen XIII (a transmembrane collagen) seems to be a low affinity ligand, and negative binding results have been published with collagens XIV (FACIT) and XVII (a transmembrane collagen; COL15 domain). In general α2β1 integrin is considered to favor fibril-forming collagens over other collagen subtypes. Integrin α2β1 can also bind to collagen I fibrils. However, in tissues collagen fibrils are often covered with other proteins and proteoglycans, and it is not clear whether in vivo α2β1 or other collagen receptors mediate cell adhesion directly to the collagen fibrils. Instead, some in vitro observations suggest that α2β1 could regulate the formation of new collagen fibrils. The binding preference of α2β1 to collagen subtypes seems to be different when compared to the other major collagen receptor, α1β1 integrin. However, α11β1 may be more similar to α2β1 as a receptor for fibril-forming collagens (Heino 2007; Herr and Farndale 2009; Leitinger 2011).

In addition to collagens, α2β1 can recognize a large number of other proteins, including different members of the laminin family and proteoglycans, such as decorin, endorepellin (a fragment of perlecan), and lumican. Tenascin C, chondroadherin, matrix metalloproteinase 1, E-cadherin, and collectin-family members (C1q complement protein, mannose-binding lectin, surfactant protein A) have been reported to be ligands for α2β1 integrin (Heino 2007; Herr and Farndale 2009; Madamanchi et al. 2014).

Pathogens binding to α2β1 include echovirus-1 and rotavirus. These viruses use α2β1 as their cellular receptor and may take advantage of the integrin-mediated endocytosis mechanisms. Group A Streptococcus express a collagenous protein, named as Scl1 that is a ligand for α2β1. Snake venoms are known to contain toxins, such as EMS16, rhodocetin, and VP12, which block α2β1 function (Eble 2010).

Signaling Function

Like all integrins, also α2β1 can have several different conformation based functional states (Arnaout et al. 2007; Luo et al. 2007). Inactivated α2β1 is a low avidity collagen receptor, but can still attach to large ligands, for example, human echovirus 1. Intracellular proteins, such as talin or kindlins, can bind to the cytoplasmic domain of β1 subunit and activate the integrin (Legate and Fässler 2009). Ligand binding leads to the opening of the α2I domain, further changes in the conformation of the β1 subunit and finally to the separation of α and β legs (Arnaout et al. 2007; Luo et al. 2007).

After binding to extracellular matrix (ECM), α2β1 is concentrated to focal adhesion sites. The cytoplasmic domain of β1 subunit binds to cytoskeleton associated proteins, including talin, filamin, myosin, and tensin (Legate and Fässler 2009). Signaling and adapter proteins, such as focal adhesion kinase (FAK), integrin linked kinase (ILK, a pseudokinase/adapter protein), Yes, and Lyn, can bind to β1 cytoplasmic domain and trigger further signaling events (Legate and Fässler 2009). Much less is known about the putative α2 cytoplasmic domain binding proteins. At least F-actin, calreticulin, Rap21, and vimentin have been reported to interact with α2 subunit. Deletion of α2 tail does not inhibit collagen binding, but leads to ligand-independent accumulation of the receptor to focal adhesion sites, suggesting that α2 tail may control the function and interactions of β1 cytoplasmic domain.

In various cell culture models, α2β1 signaling has been connected to the activation of p38 and ERK MAP kinases, p27kip, Osf2, protein phosphatase 2A (PP2A), Akt, PI-3-kinase, Rac-1, and vav-2. In cell culture experiments α2β1 regulates cell proliferation, differentiation, migration, survival, ECM synthesis, and matrix degradation (Ivaska and Heino 2011; Madamanchi et al. 2014; Heino 2014).

The role of α2β1 signaling in platelets has been studied in detail. The major platelet collagen receptors, glycoprotein VI and α2β1, seem to regulate each other’s activity and at least partially the same signaling proteins, including Src, Syk, SLP-76, and phospholipase Cγ2. Integrin α2β1 can also regulate Ca2+ concentration inside platelets. It is has been reported to induce specific rapid α-like peaks, but not longer-lasting γ-like peaks.

In general, the integrins have the ability to modify the signaling function of many growth factor receptors. They may create a proper environment for growth factor induced signaling or in some cases directly activate the growth factor receptors in a growth factor independent manner. Integrins may also orchestrate endocytosis and trafficking of growth factors receptors and regulate their number on cell surface (Ivaska and Heino 2011).

Function in Vivo

The in vivo function of α2β1 integrin has been analyzed by using knockout mice or by studying the effect of function blocking antibodies in various mouse models. The results from experiments utilizing null animals or specific inhibitors have in some cases produced conflicting results, which makes its sometimes difficult to estimate the actual biological function of α2β1 integrin. In human the role of α2β1 has been estimated in epidemiological studies that have been able to connect this receptor to specific human diseases.

In general α2 null mice are viable and fertile and harbor no obvious developmental defects. The architecture of mammary glands may be slightly altered. Their platelets show reduced response to collagen and slightly prolonged bleeding time. In addition, in an endothelial injury model, the lack of α2β1 integrin inhibits thrombosis. The small defects detected in the platelet function are in full agreement with the epidemiological data concerning human thrombotic diseases. Due to genetic polymorphism, some individuals have elevated levels of α2β1 integrin on platelets. These persons may have elevated risk for myocardial infarction or cerebrovascular stroke. Furthermore, the medical literature knows one individual lacking α2β1 integrin on platelets and suffering from a mild bleeding disorder. Thus, α2β1 seems to be a functional collagen receptor on platelets. However, its relative importance, when compared to other collagen-binding mechanisms, namely, GPVI receptor or von Willebrand factor/GPIα system, has sometimes been challenged (Varga-Szabo et al. 2008).

In α2-deficient mice, increased angiogenesis has been reported during wound healing. Similarly, cancer-related angiogenesis is enhanced. Paradoxically, antibodies against α2 can inhibit cancer-related angiogenesis. Furthermore, endorepellin, an inhibitor of angiogenesis seems to work in an α2β1-dependent manner. Similar controversy has been reported in the studies focused on the role of αV integrins in angiogenesis. The reason for this discrepancy is not clear, but integrins may orchestrate the endocytosis and trafficking of growth factor receptors and have indirect effects on many biological processes (Eckes et al. 2006; Ivaska and Heino 2011; Johnson et al. 2009; Madamanchi et al. 2014).

Antibodies against α2β1 integrin can block the function of immunological cells, and the null animals have defects in both native and acquired immunity (Eckes et al. 2006; Johnson et al. 2009; Madamanchi et al. 2014).

In human cancer, α2β1 integrin expression has been associated to cancer chemoresistance especially in hematological malignancies originating from the T cell lineage. Integrin α2β1 is a marker of prostate stem cells and it has been linked to prostate cancer invasion. However, in breast cancer α2β1 expression often decreases and α2β1 may even suppress metastasis (Naci et al. 2015).

Integrin α2β1 is considered to be a putative target for drug development in thrombosis-related diseases, cancer, and inflammation.


Integrin α2 forms a heterodimer with integrin β1. α2β1 is an abundantly expressed receptor for various collagen subtypes as well as for many other ECM molecules. Based on the data from α2 null mice, as well from a human lacking α2 on platelets, the receptor participates in platelet binding to collagen. In thrombosis α2β1 acts together with another collagen receptor, namely, GPVI. Furthermore, α2β1 seems to participate in acquired as well as native immunity. The data related to the putative role of α2β1 during wound healing and angiogenesis are still incomplete. Polymorphism in ITG2A gene has been correlated to higher expression levels of α2β1 on platelets and increased risk to myocardial infarction and stroke. Integrin α2β1 is considered to be a potential drug target in thrombosis, cancer, and inflammation.


  1. Arnaout MA, Goodman SL, Xiong JP. Structure and mechanics of integrin-based cell adhesion. Curr Opin Cell Biol. 2007;19:495–507.PubMedCrossRefPubMedCentralGoogle Scholar
  2. Eble JA. Matrix biology meets toxinology. Matrix Biol. 2010;29:239–47.PubMedCrossRefGoogle Scholar
  3. Eckes B, Zweers MC, Zhang ZG, Hallinger R, Mauch C, Aumailley M, Krieg T. Mechanical tension and integrin α2β1 regulate fibroblast functions. J Investig Dermatol Symp Proc. 2006;11:66–72.PubMedCrossRefGoogle Scholar
  4. Heino J. The collagen family members as cell adhesion proteins. Bioessays. 2007;29:1001–10.PubMedCrossRefGoogle Scholar
  5. Heino J. Cellular signaling by collagen-binding integrins. Adv Exp Med Biol. 2014;819:143–55.PubMedCrossRefGoogle Scholar
  6. Herr AB, Farndale RW. Structural insights into the interactions between platelet receptors and fibrillar collagen. J Biol Chem. 2009;284:19781–5.PubMedCrossRefPubMedCentralGoogle Scholar
  7. Hynes RO. The emergence of integrins: a personal and historical perspective. Matrix Biol. 2004;23(6):333–40.PubMedCrossRefPubMedCentralGoogle Scholar
  8. Ivaska J, Heino J. Cooperation between integrins and growth factor receptors in signaling and endocytosis. Annu Rev Cell Dev Biol. 2011;27:291–320.PubMedCrossRefGoogle Scholar
  9. Johnson MS, Lu N, Denessiouk K, Heino J, Gullberg D. Integrins during evolution: evolutionary trees and model organisms. Biochim Biophys Acta. 2009;1788:779–89.PubMedCrossRefGoogle Scholar
  10. Legate KR, Fässler R. Mechanisms that regulate adaptor binding to β-integrin cytoplasmic tails. J Cell Sci. 2009;122:187–98.PubMedCrossRefGoogle Scholar
  11. Leitinger B. Transmembrane collagen receptors. Annu Rev Cell Dev Biol. 2011;27:265–90.PubMedCrossRefGoogle Scholar
  12. Luo BH, Carman CV, Springer TA. Structural basis of integrin regulation and signaling. Annu Rev Immunol. 2007;25:619–47.PubMedCrossRefPubMedCentralGoogle Scholar
  13. Madamanchi A, Santoro SA, Zutter MM. α2β1 Integrin. Adv Exp Med Biol. 2014;819:41–60.PubMedCrossRefGoogle Scholar
  14. Naci D, Vuori K, Aoudjit F. Alpha2beta1 integrin in cancer development and chemoresistance. Semin Cancer Biol. 2015;35:145–53.PubMedCrossRefGoogle Scholar
  15. Varga-Szabo D, Pleines I, Nieswandt B. Cell adhesion mechanisms in platelets. Arterioscler Thromb Vasc Biol. 2008;28:403–12.PubMedCrossRefGoogle Scholar
  16. Zeltz C, Gullberg D. The integrin-collagen connection-a glue for tissue repair? J Cell Sci. 2016;129:653–64.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of BiochemistryUniversity of TurkuTurkuFinland