Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Integrin α1 (ITGA1)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_556


Historical Background

Integrin α1 subunit forms a heterodimer with integrin β1 subunit and acts as a cellular collagen receptor. α1β1 is one of the first integrins found, and it was originally described as T lymphocyte very late activation antigen-1 (VLA-1). Today the human integrin family is known to contain 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 connected to cytoskeletal filaments and also to multiple cellular signaling pathways (Hynes 2004).


Integrins are single-pass type I membrane glycoproteins. Integrin α1 subunit contains short intracellular domain, transmembrane anchor, and an extracellular part, composed of α1I, β-propeller, thigh, calf-1, and calf-2 domains (Fig. 1). Thus, α1 belongs to a subgroup of integrins that contain an αI domain (inserted domain that is often called as A domain, based on its structural similarity with von Willebrand factor A domain). Integrin αI domain adopts a dinucleotide-binding or Rossmann fold and binds to ligands using a magnesium-containing metal ion-dependent coordination site (MIDAS). The formation of α1–β1 complex is based on the non-covalent binding of β-propeller domain (α subunit) to β1I domain (β subunit). Together with the α1I, these two domains form the “head” part. The “leg” part of α1 subunit is composed of thigh, calf-1, and calf-2 domains, while hybrid, PSI, four I-EGF (1–4), and β-tail domains form the β1 leg part. The leg parts can be bended in “knees” between thigh and calf-1 domain (α subunit) or between hybrid and I-EGF-1 domain (β subunit) (Luo et al. 2007; Arnaout et al. 2007).
Integrin α1 (ITGA1), Fig. 1

Integrin α1 (ITGA1) Domain structure of integrin α1β1, a collagen receptor. αI (αA) domain is a high affinity binding site for basement membrane collagen IV, 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

Based on their structure and phylogeny, human integrin α subunits can be divided into four different subfamilies. Nine out of 18 human integrin α subunits belong to the group of the αI domain integrins. Integrin αI domains are only found in chordates. The αI domain integrins can be further divided into leukocyte integrins and collagen receptor integrins. Integrin α1β1 forms together with three other heterodimers, namely, α2β1, α10β1, and α11β1, the collagen receptor subfamily. The biological functions of the integrin-type collagen receptors are often related to immunity and tissue regeneration. (Johnson et al. 2009; Zeltz and Gullberg 2016).

Integrin α1 is expressed on mesenchymal cells, including fibroblasts, chondrocytes, osteoblasts, endothelial cells, and smooth muscle cells. It cannot exist on cell surface alone, but it is always in complex with integrin β1 subunit. Many inflammatory cells, including activated T lymphocytes, natural killer cells, and monocytes/macrophages are α1 positive (Ben-Horin and Bank 2004).


Integrin α1β1 is a high-avidity receptor for several collagen subtypes. The collagen family contains 28 members, and for most of the subtypes, detailed information about receptor interactions is not available. Many published reports have emphasized the role of α1β1 as a receptor for basement membrane type IV collagen, whereas the receptor seems to have a relative low avidity to fibril-forming collagen subtypes (I, II, III, V). Thus, its preference to collagen subtypes seems to be different when compared to the other major collagen receptor, α2β1 integrin. Like all collagen receptor integrins, α1β1 can recognize the triple helical motif formed by peptides containing a GFOGER (O = hydroxyproline) sequence or similar GLOGER and GASGER motifs. In addition to the GFOGER site, α1β1 binds with high affinity to a separate triple helical motif found in collagen IV. In this site, α1I domain recognizes two aspartic acid and one arginine residue, all located in different α chain. Thus, α1β1 may bind to fibril-forming and basement membrane collagens with a different mechanism. α1β1 has also been reported to recognize network-forming collagens (VIII), fibril-associated collagens with interruptions in triple helix (FACITs; IX, XVI), and transmembrane collagens (XIII). Presently, it is not possible to estimate what collagen subtypes are acting as the main α1β1 ligands during different physiological processes linked to this receptor.

Proteolytic fragments of ECM proteins have been reported to regulate biological processes. The cellular responses are often mediated by integrin-type receptors. The NC1 domain of α1(IV) collagen α-chain, also called as arresten, can be proteolytically released from collagen IV and has anti-angiogenic properties. Arresten has been reported to bind to α1β1, and this may explain the mechanism of its function (Heino 2007; Leitinger 2011; Herr and Farndale 2009).

Other ligands of α1β1 integrin include various laminin subtypes. Laminin is the main structural protein in basement membranes. Matrilin-1, a cartilage ECM protein, and galectin-8, a β-galactoside binding lectin, can also bind to α1β1. Semaphorin 7A (Sema7A) is a glycosylphosphatidylinositol-linked membrane-associated protein, known to have two receptors, plexin C1 and α1β1 integrin. Sema7A is expressed on neural cells, activated T cells, platelets, skin keratinocytes, and fibroblasts. In axon guidance, T-cell-activated cytokine production in monocytes and macrophages, as well as in the attachment of skin melanocytes, the effects of SemaA7 are dependent on β1 integrins. In addition to physiological ligands, snake venom KTS-/RTS-disintegrins can block α1β1 function (Eble 2010; Ivaska and Heino 2011).

Signaling Function

Like all integrins, also α1β1 may have several different conformation-based functional states (Luo et al. 2007; Arnaout et al. 2007). Proteins, such as talin or kindlins, can bind to the cytoplasmic domain of β1 subunit and activate the integrin. The activation is associated to a conformational change from a bent to an extended state, in which the integrin is standing tall on cell surface. Ligand binding to αI domain is considered to lead to the opening of the domain, further changes in the conformation of the β1 subunit, and finally to the separation of α and β legs. After binding to ECM, α1β1 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).

Detailed mutation-based analysis has revealed the important role of α1 cytoplasmic tail for α1β1-mediated cellular functions and for the activation of p38 and ERK MAP kinase pathways. T-cell protein tyrosine phosphatase (TCPTP) is reported to bind to α1 cytoplasmic domain and negatively regulate epidermal growth factor (EGF) receptor function (Ivaska and Heino 2011).

Integrin α1β1 has been reported to regulate several signaling proteins and pathways. It can activate tyrosine kinases Fyn and Lck, which lead to phosphorylation of Shc. In arteries, α1β1 plays an important role in the shear-stress-induced activation of Akt and PI 3-kinase. Furthermore, the production of reactive oxygen species (ROS) is controlled by α1β1 (Ivaska and Heino 2011; Heino 2014).

In addition to their own signaling function, the integrins have the ability to modify the signaling by many growth factor receptors. Often integrins are essential for the formation of molecular platforms that are needed for growth factor-dependent activation of growth factor receptors. In some cases, integrins can directly activate the growth factor receptors in a growth factor-independent manner. Furthermore, integrins may also regulate the recycling of growth factor receptors and regulate their number on cell surface (Ivaska and Heino 2011).

Function In Vivo

The in vivo function of α1β1 integrin has been analyzed by using knockout mice or by studying the effect of function-blocking antibodies in various mouse models. In general, α1-null mice are viable and fertile and harbor no remarkable developmental defects. Still, these animals are not fully normal since their skin is hypocellular, proposing that stem cell proliferation may be affected. The turnover rate of the skin collagenous matrix is also altered, confirming the in vitro observations that α1β1 is a negative feedback regulator of collagen synthesis. Despite the increased collagen synthesis, α1-knockout animals develop no obvious fibrotic skin disease, because the lack of α1 also seems to lead to increased production of matrix metalloproteinase. Conforming the affected regulation of collagen synthesis, α1-deficient mice are more sensitive to adriamycin-induced kidney fibrosis than their normal littermates.

The healing of bone fractures is compromised in α1-null mice due to the defected proliferation of bone marrow mesenchymal stem cells. Accordingly, α1-deficient animals seem to develop aging-dependent osteoarthritis. These observations support the idea that one of the main functions of α1β1 integrin is to support the proliferation of specific mesenchymal stem cell populations. In α1-null animals, also cancer-related angiogenesis, normal kidney function, and retina development are affected. Severity of obesity-induced fatty liver disease is attenuated in integrin α1-knockout mice (Heino 2007; Pozzi et al. 2009; Johnson et al. 2009; Ivaska and Heino 2011; Gardner 2014; Zeltz and Gullberg 2016).

Antibodies against α1 integrin can inhibit angiogenesis, lymphangiogenesis, and inflammation. α1β1 seems to augment T-cell activation and proliferation, and the important role of α1β1 integrin for cell-mediated immunity has been shown in numerous animal experiments, including models for graft-versus-host disease, arthritis, colitis, allergen-induced bronchoconstriction, and glomerulonephritis. Integrin α1β1 may also play an important role in the pathogenesis of Alport syndrome, since in Alport mice, collagen XIII in kidney endothelial cells mediates the selective recruitment of α1β1 integrin-positive monocytes (Ben-Horin and Bank 2004).

The important role of α1β1 integrin in the maintenance of bone metabolism is also proposed based on the observation that polymorphism in integrin α1 gene is associated with osteoporosis and related fracture risk in Korean females.


Integrin α1 subunit forms a heterodimer with integrin β1 subunit. Integrin α1β1 is an abundantly expressed mesenchymal collagen receptor that predominantly mediates cellular interactions with basement membrane collagen IV. Based on in vivo experiments with specific inhibitors and knockout animals, α1β1 has multiple physiological roles. First, α1β1 supports the proliferation of cells, e.g., mesenchymal stem cells. Second, α1β1 regulates extracellular matrix turnover, including the synthesis of collagen and matrix metalloproteinases. Third, inflammatory cells, especially T cells and monocytes, use this collagen receptor. Integrin α1β1 is a potential target molecule for drug development in inflammation and fibrosis.


  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. Ben-Horin S, Bank I. The role of very late antigen-1 in immune-mediated inflammation. Clin Immunol. 2004;113:119–29.PubMedCrossRefGoogle Scholar
  3. Eble JA. Matrix biology meets toxinology. Matrix Biol. 2010;29:239–47.PubMedCrossRefGoogle Scholar
  4. Gardner H. Integrin α1β1. Adv Exp Med Biol. 2014;819:21–39.PubMedCrossRefGoogle Scholar
  5. Heino J. The collagen family members as cell adhesion proteins. Bioessays. 2007;29:1001–10.PubMedCrossRefGoogle Scholar
  6. Heino J. Cellular signaling by collagen-binding integrins. Adv Exp Med Biol. 2014;819:143–55.PubMedCrossRefGoogle Scholar
  7. Herr AB, Farndale RW. Structural insights into the interactions between platelet receptors and fibrillar collagen. J Biol Chem. 2009;284:19781–5.PubMedCrossRefPubMedCentralGoogle Scholar
  8. Hynes RO. The emergence of integrins: a personal and historical perspective. Matrix Biol. 2004;23:333–40.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 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
  10. Johnson MS, Lu N, Denessiouk K, Heino J, Gullberg D. Integrins during evolution: evolutionary trees and model organisms. Biochim Biophys Acta. 1788;2009:779–89.Google Scholar
  11. Legate KR, Fässler R. Mechanisms that regulate adaptor binding to beta-integrin cytoplasmic tails. J Cell Sci. 2009;122:187–98.PubMedCrossRefGoogle Scholar
  12. Leitinger B. Transmembrane collagen receptors. Annu Rev Cell Dev Biol. 2011;27:265–90.PubMedCrossRefGoogle Scholar
  13. Luo BH, Carman CV, Springer TA. Structural basis of integrin regulation and signaling. Annu Rev Immunol. 2007;25:619–47.PubMedCrossRefPubMedCentralGoogle Scholar
  14. Pozzi A, Voziyan PA, Hudson BG, Zent R. Regulation of matrix synthesis, remodeling and accumulation in glomerulosclerosis. Curr Pharm Des. 2009;15:1318–33.PubMedCrossRefGoogle Scholar
  15. Zeltz C, Gullberg D. The integrin-collagen connection-a glue for tissue repair? J Cell Sci. 2016;129:653–64.PubMedCrossRefGoogle Scholar

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of BiochemistryUniversity of TurkuTurkuFinland