Integrins are unusual signalling proteins that function to signal both from the extracellular environment into the cell, but also from the cytoplasm to the external of the cell. The intracellular signalling cascades associated with integrin activation focus on protein kinase activities, such as focal adhesion kinase and Src. Based on this association between extracellular signals and intracellular protein kinase activity, we have chosen to include integrins in the 'Catalytic receptors' section of the database until more stringent criteria from NC-IUPHAR allows precise definition of their classification.

Integrins are heterodimeric entities, composed of α and β subunits, each 1TM proteins, which bind components of the extracellular matrix or counter-receptors expressed on other cells. One class of integrin contains an inserted domain (I) in its α subunit, and if present (in α1, α2, α10, α11, αD, αE, αL, αM and αX), this I domain contains the ligand binding site. All β subunits possess a similar I-like domain, which has the capacity to bind ligand, often recognising the RGD motif. The presence of an α subunit I domain precludes ligand binding through the β subunit. Integrins provide a link between ligand and the actin cytoskeleton (through typically short intracellular domains). Integrins bind several divalent cations, including a Mg²⁺ ion in the I or I-like domain that is essential for ligand binding. Other cation binding sites may regulate integrin activity or stabilise the 3D structure. Integrins regulate the activity of particular protein kinases, including focal adhesion kinase and integrin-linked kinase. Cellular activation regulates integrin ligand affinity via inside-out signalling and ligand binding to integrins can regulate cellular activity via outside-in signalling.

Several drugs that target integrins are in clinical use including: (1) abciximab (αIIbβ3) for short term prevention of coronary thrombosis, (2) vedolizumab (α4β7) to reduce gastrointestinal inflammation, and (3) natalizumab (α4β1) in some cases of severe multiple sclerosis.

Integrin ligands
Collagen is the most abundant protein in metazoa, rich in glycine and proline residues, made up of cross-linked triple helical structures, generated primarily by fibroblasts. Extensive post-translational processing is conducted by prolyl and lysyl hydroxylases, as well as transglutaminases. Over 40 genes for collagen-α subunits have been identified in the human genome. The collagen-binding integrins α1β1, α2β1, α10β1 and α11β1 recognise a range of triple-helical peptide motifs including GFOGER (O = hydroxyproline), a synthetic peptide derived from the primary sequence of collagen I (COL1A1 (COL1A1, P02452)) and collagen II (COL2A1 (COL2A1, P02458)).

Laminin is an extracellular glycoprotein composed of α, β and γ chains, for which five, four and three genes, respectively, are identified in the human genome. It binds to α1β1, α2β1, α3,β1, α7β1 and α6β4 integrins10.

fibrinogen (FGA, FGB, FGG, P02671, P02675, P02679) is a glycosylated hexamer composed of two α (FGA, P02671), two β (FGB, P02675) and two γ (FGG, P02679,) subunits, linked by disulphide bridges. It is found in plasma and alpha granules of platelets. It forms cross-links between activated platelets mediating aggregation by binding αIIbβ3; proteolysis by thrombin cleaves short peptides termed fibrinopeptides to generate fibrin, which polymerises as part of the blood coagulation cascade.

fibronectin (FN1, P02751) is a disulphide-linked homodimer found as two major forms; a soluble dimeric form found in the plasma and a tissue version that is polymeric, which is secreted into the extracellular matrix by fibroblasts. Splice variation of the gene product (FN1, P02751) generates multiple isoforms.

vitronectin (VTN, P04004) is a serum glycoprotein and extracellular matrix protein which is found either as a monomer or, following proteolysis, a disulphide -linked dimer.

osteopontin (SPP1, P10451) forms an integral part of the mineralized matrix in bone, where it undergoes extensive post-translation processing, including proteolysis and phosphorylation.

von Willebrand factor (VWF, P04275) is a glycoprotein synthesised in vascular endothelial cells as a disulphide-linked homodimer, but multimerises further in plasma and is deposited on vessel wall collagen as a high molecular weight multimer. It is responsible for capturing platelets under arterial shear flow (via GPIb) and in thrombus propagation (via integrin αIIbβ3).

* Key recommended reading is highlighted with an asterisk

Anthis NJ, Campbell ID. (2011) The tail of integrin activation. Trends Biochem Sci, 36 (4): 191-8. [PMID:21216149]

Bledzka K, Smyth SS, Plow EF. (2013) Integrin αIIbβ3: from discovery to efficacious therapeutic target. Circ Res, 112 (8): 1189-200. [PMID:23580774]

Cavallaro U, Dejana E. (2011) Adhesion molecule signalling: not always a sticky business. Nat Rev Mol Cell Biol, 12 (3): 189-97. [PMID:21346732]

* Clemetson KJ. (2017) The origins of major platelet receptor nomenclature. Platelets, 28 (1): 40-42. [PMID:27715379]

Cox D, Brennan M, Moran N. (2010) Integrins as therapeutic targets: lessons and opportunities. Nat Rev Drug Discov, 9 (10): 804-20. [PMID:20885411]

* Emsley J, Knight CG, Farndale RW, Barnes MJ, Liddington RC. (2000) Structural basis of collagen recognition by integrin alpha2beta1. Cell, 101 (1): 47-56. [PMID:10778855]

Hamaia S, Farndale RW. (2014) Integrin recognition motifs in the human collagens. Adv Exp Med Biol, 819: 127-42. [PMID:25023172]

* Hamidi H, Pietilä M, Ivaska J. (2016) The complexity of integrins in cancer and new scopes for therapeutic targeting. Br J Cancer, 115 (9): 1017-1023. [PMID:27685444]

Hogg N, Patzak I, Willenbrock F. (2011) The insider's guide to leukocyte integrin signalling and function. Nat Rev Immunol, 11 (6): 416-26. [PMID:21597477]

* Horton ER, Humphries JD, James J, Jones MC, Askari JA, Humphries MJ. (2016) The integrin adhesome network at a glance. J Cell Sci, 129 (22): 4159-4163. [PMID:27799358]

Hu P, Luo BH. (2013) Integrin bi-directional signaling across the plasma membrane. J Cell Physiol, 228 (2): 306-12. [PMID:22767296]

Humphries JD, Byron A, Humphries MJ. (2006) Integrin ligands at a glance. J Cell Sci, 119 (Pt 19): 3901-3. [PMID:16988024]

Hynes RO. (2002) Integrins: bidirectional, allosteric signaling machines. Cell, 110 (6): 673-87. [PMID:12297042]

Ivaska J, Heino J. (2011) Cooperation between integrins and growth factor receptors in signaling and endocytosis. Annu Rev Cell Dev Biol, 27: 291-320. [PMID:21663443]

Kim C, Ye F, Ginsberg MH. (2011) Regulation of integrin activation. Annu Rev Cell Dev Biol, 27: 321-45. [PMID:21663444]

* Ley K, Rivera-Nieves J, Sandborn WJ, Shattil S. (2016) Integrin-based therapeutics: biological basis, clinical use and new drugs. Nat Rev Drug Discov, 15 (3): 173-83. [PMID:26822833]

* Manninen A, Varjosalo M. (2017) A proteomics view on integrin-mediated adhesions. Proteomics, 17 (3-4). [PMID:27723259]

Park YK, Goda Y. (2016) Integrins in synapse regulation. Nat Rev Neurosci, 17 (12): 745-756. [PMID:27811927]

* Raab-Westphal S, Marshall JF, Goodman SL. (2017) Integrins as Therapeutic Targets: Successes and Cancers. Cancers (Basel), 9 (9). [PMID:28832494]

Roca-Cusachs P, Iskratsch T, Sheetz MP. (2012) Finding the weakest link: exploring integrin-mediated mechanical molecular pathways. J Cell Sci, 125 (Pt 13): 3025-38. [PMID:22797926]

Shattil SJ, Kim C, Ginsberg MH. (2010) The final steps of integrin activation: the end game. Nat Rev Mol Cell Biol, 11 (4): 288-300. [PMID:20308986]

Weber GF, Bjerke MA, DeSimone DW. (2011) Integrins and cadherins join forces to form adhesive networks. J Cell Sci, 124 (Pt 8): 1183-93. [PMID:21444749]

Wickström SA, Fässler R. (2011) Regulation of membrane traffic by integrin signaling. Trends Cell Biol, 21 (5): 266-73. [PMID:21440440]

Wu X, Reddy DS. (2012) Integrins as receptor targets for neurological disorders. Pharmacol Ther, 134 (1): 68-81. [PMID:22233753]

1. Anderson NA, Campos S, Butler S, Copley RCB, Duncan I, Harrison S, Le J, Maghames R, Pastor-Garcia A, Pritchard JM et al.. (2019) Discovery of an Orally Bioavailable Pan αv Integrin Inhibitor for Idiopathic Pulmonary Fibrosis. J Med Chem, 62 (19): 8796-8808. [PMID:31497959]

2. Barrett TN, Taylor JA, Barker D, Procopiou PA, Thompson JDF, Barrett J, Le J, Lynn SM, Pogany P, Pratley C et al.. (2019) Profile of a Highly Selective Quaternized Pyrrolidine Betaine α_vβ₆ Integrin Inhibitor-(3S)-3-(3-(3,5-Dimethyl-1H-pyrazol-1-yl)phenyl)-4-((1S and 1R,3R)-1-methyl-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-ium-1-yl)butanoate Synthesized by Stereoselective Methylation. J Med Chem, 62 (16): 7543-7556. [PMID:31381331]

3. Bhaskar V, Fox M, Breinberg D, Wong MH, Wales PE, Rhodes S, DuBridge RB, Ramakrishnan V. (2008) Volociximab, a chimeric integrin alpha5beta1 antibody, inhibits the growth of VX2 tumors in rabbits. Invest New Drugs, 26 (1): 7-12. [PMID:17786386]

4. Bhaskar V, Zhang D, Fox M, Seto P, Wong MH, Wales PE, Powers D, Chao DT, Dubridge RB, Ramakrishnan V. (2007) A function blocking anti-mouse integrin alpha5beta1 antibody inhibits angiogenesis and impedes tumor growth in vivo. J Transl Med, 5: 61. [PMID:18042290]

5. Breitenstein W, Huerzeler M, Kelly T, Mancuso R, Schneider G, Weitz-Schmidt G. (2015) Small molecule lfa-1 inhibitors. Patent number: WO2015189265. Assignee: Allocyte Pharmaceuticals Ag. Priority date: 12/06/2014. Publication date: 17/12/2015.

6. Coller BS, Knight DM. (1999) Method of antithrombotic therapy using anti-GPIIb/IIIa antibodies or fragments thereof, including c7E3. Patent number: US5976532. Assignee: Centocor, Inc.. Priority date: 18/05/1988. Publication date: 02/11/1999.

7. Derkach DN, Wadekar SA, Perkins KB, Rousseau E, Dreiza CM, Cheung-Flynn J, Ramos HC, Ugarova TP, Sheller MR. (2010) RGD-dependent binding of TP508 to integrin alphavbeta3 mediates cell adhesion and induction of nitric oxide. Thromb Haemost, 104 (1): 172-82. [PMID:20508901]

8. Eldred CD, Evans B, Hindley S, Judkins BD, Kelly HA, Kitchin J, Lumley P, Porter B, Ross BC, Smith KJ et al.. (1994) Orally active non-peptide fibrinogen receptor (GpIIb/IIIa) antagonists: identification of 4-[4-[4-(aminoiminomethyl)phenyl]-1-piperazinyl]-1-piperidineacetic acid as a long-acting, broad-spectrum antithrombotic agent. J Med Chem, 37 (23): 3882-5. [PMID:7966149]

9. Fukase H, Kajioka T, Oikawa I, Ikeda N, Furuie H. (2020) AJM300, a novel oral antagonist of α4-integrin, sustains an increase in circulating lymphocytes: A randomised controlled trial in healthy male subjects. Br J Clin Pharmacol, 86 (3): 591-600. [PMID:31658381]

10. Goodman SL, Hölzemann G, Sulyok GA, Kessler H. (2002) Nanomolar small molecule inhibitors for alphav(beta)6, alphav(beta)5, and alphav(beta)3 integrins. J Med Chem, 45 (5): 1045-51. [PMID:11855984]

11. Grove RA, Shackelford S, Sopper S, Pirruccello S, Horrigan J, Havrdova E, Gold M, Graff O. (2013) Leukocyte counts in cerebrospinal fluid and blood following firategrast treatment in subjects with relapsing forms of multiple sclerosis. Eur J Neurol, 20 (7): 1032-42. [PMID:23419064]

12. Henderson NC, Arnold TD, Katamura Y, Giacomini MM, Rodriguez JD, McCarty JH, Pellicoro A, Raschperger E, Betsholtz C, Ruminski PG et al.. (2013) Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med, 19 (12): 1617-24. [PMID:24216753]

13. Hijazi Y, Welker H, Dorr AE, Tang JP, Blain R, Renzetti LM, Abbas R. (2004) Pharmacokinetics, safety, and tolerability of R411, a dual alpha4beta1-alpha4beta7 integrin antagonist after oral administration at single and multiple once-daily ascending doses in healthy volunteers. J Clin Pharmacol, 44 (12): 1368-78. [PMID:15545307]

14. Hutchinson JH, Halczenko W, Brashear KM, Breslin MJ, Coleman PJ, Duong LT, Fernandez-Metzler C, Gentile MA, Fisher JE, Hartman GD et al.. (2003) Nonpeptide alphavbeta3 antagonists. 8. In vitro and in vivo evaluation of a potent alphavbeta3 antagonist for the prevention and treatment of osteoporosis. J Med Chem, 46 (22): 4790-8. [PMID:14561098]

15. Jardieu PM, Presta LG. (2004) Method of treatment using humanized anti-CD11a antibodies. Patent number: US6703018. Assignee: Genentech, Inc.. Priority date: 27/11/1996. Publication date: 19/03/2004.

16. Lee Y, Kang DK, Chang SI, Han MH, Kang IC. (2004) High-throughput screening of novel peptide inhibitors of an integrin receptor from the hexapeptide library by using a protein microarray chip. J Biomol Screen, 9 (8): 687-94. [PMID:15634795]

17. Lin Kc, Ateeq HS, Hsiung SH, Chong LT, Zimmerman CN, Castro A, Lee WC, Hammond CE, Kalkunte S, Chen LL et al.. (1999) Selective, tight-binding inhibitors of integrin alpha4beta1 that inhibit allergic airway responses. J Med Chem, 42 (5): 920-34. [PMID:10072689]

18. Liu G, Link JT, Pei Z, Reilly EB, Leitza S, Nguyen B, Marsh KC, Okasinski GF, von Geldern TW, Ormes M et al.. (2000) Discovery of novel p-arylthio cinnamides as antagonists of leukocyte function-associated antigen-1/intracellular adhesion molecule-1 interaction. 1. Identification of an additional binding pocket based on an anilino diaryl sulfide lead. J Med Chem, 43 (21): 4025-40. [PMID:11052808]

19. Makino S, Okuzumi T, Yoshimura T, Satake Y, Suzuki N, Izawa H, Sagi K, Chiba A, Nakanishi E, Murata M et al.. (2011) New phenylalanine derivatives. Patent number: US20110065918A1. Assignee: EA Pharma Co Ltd. Priority date: 18/08/2000. Publication date: 17/03/2011.

20. Marcinkiewicz C, Weinreb PH, Calvete JJ, Kisiel DG, Mousa SA, Tuszynski GP, Lobb RR. (2003) Obtustatin: a potent selective inhibitor of alpha1beta1 integrin in vitro and angiogenesis in vivo. Cancer Res, 63 (9): 2020-3. [PMID:12727812]

21. Matsuno H, Stassen JM, Vermylen J, Deckmyn H. (1994) Inhibition of integrin function by a cyclic RGD-containing peptide prevents neointima formation. Circulation, 90 (5): 2203-6. [PMID:7955174]

22. Miller MW, Basra S, Kulp DW, Billings PC, Choi S, Beavers MP, McCarty OJ, Zou Z, Kahn ML, Bennett JS et al.. (2009) Small-molecule inhibitors of integrin alpha2beta1 that prevent pathological thrombus formation via an allosteric mechanism. Proc Natl Acad Sci USA, 106 (3): 719-24. [PMID:19141632]

23. Nissinen L, Koivunen J, Käpylä J, Salmela M, Nieminen J, Jokinen J, Sipilä K, Pihlavisto M, Pentikäinen OT, Marjamäki A et al.. (2012) Novel α2β1 integrin inhibitors reveal that integrin binding to collagen under shear stress conditions does not require receptor preactivation. J Biol Chem, 287 (53): 44694-702. [PMID:23132859]

24. No authors listed. (2004) Natalizumab: AN 100226, anti-4alpha integrin monoclonal antibody. Drugs R D, 5 (2): 102-7. [PMID:15293871]

25. Pan WJ, Hsu H, Rees WA, Lear SP, Lee F, Foltz IN, Rathanaswami P, Manchulenko K, Chan BM, Zhang M et al.. (2013) Pharmacology of AMG 181, a human anti-α4 β7 antibody that specifically alters trafficking of gut-homing T cells. Br J Pharmacol, 169 (1): 51-68. [PMID:23425116]

26. Pepinsky RB, Mumford RA, Chen LL, Leone D, Amo SE, Riper GV, Whitty A, Dolinski B, Lobb RR, Dean DC et al.. (2002) Comparative assessment of the ligand and metal ion binding properties of integrins alpha9beta1 and alpha4beta1. Biochemistry, 41 (22): 7125-41. [PMID:12033947]

27. Ponath PD, Ringler DJ, ST, Newman W, Saldanha J, Bendig MM. (2006) Humanized immunoglobulin reactive with α4β7 integrin. Patent number: US7147851 B1. Assignee: Millennium Pharmaceuticals, Inc.. Priority date: 15/08/1996. Publication date: 12/12/2006.

28. Sato-Nishiuchi R, Nakano I, Ozawa A, Sato Y, Takeichi M, Kiyozumi D, Yamazaki K, Yasunaga T, Futaki S, Sekiguchi K. (2012) Polydom/SVEP1 is a ligand for integrin α9β1. J Biol Chem, 287 (30): 25615-30. [PMID:22654117]

29. Scarborough RM, Gretler DD. (2000) Platelet glycoprotein IIb-IIIa antagonists as prototypical integrin blockers: novel parenteral and potential oral antithrombotic agents. J Med Chem, 43 (19): 3453-73. [PMID:10999999]

30. Stefanich EG, Danilenko DM, Wang H, O'Byrne S, Erickson R, Gelzleichter T, Hiraragi H, Chiu H, Ivelja S, Jeet S et al.. (2011) A humanized monoclonal antibody targeting the β7 integrin selectively blocks intestinal homing of T lymphocytes. Br J Pharmacol, 162 (8): 1855-70. [PMID:21232034]

31. Trstenjak U, Ilaš J, Kikelj D. (2013) Low molecular weight dual inhibitors of factor Xa and fibrinogen binding to GPIIb/IIIa with highly overlapped pharmacophores. Eur J Med Chem, 64: 302-13. [PMID:23644213]

32. Wolf C, Sidhu J, Otoul C, Morris DL, Cnops J, Taubel J, Bennett B. (2013) Pharmacodynamic consequences of administration of VLA-4 antagonist CDP323 to multiple sclerosis subjects: a randomized, double-blind phase 1/2 study. PLoS One, 8 (3): e58438. [PMID:23472197]

33. Wu H, Gao C. (2010) Eph receptor Fc variants with enhanced antibody dependent cell-mediated cytotoxicity activity. Patent number: US7659374. Assignee: Medimmune, Llc. Priority date: 16/08/2004. Publication date: 09/02/2010.

34. Yao N, Xiao W, Wang X, Marik J, Park SH, Takada Y, Lam KS. (2009) Discovery of targeting ligands for breast cancer cells using the one-bead one-compound combinatorial method. J Med Chem, 52 (1): 126-33. [PMID:19055415]

35. Yasuda T, Gold HK, Kohmura C, Guerrero L, Yaoita H, Fallon JT, Bunting S, Collen D. (1993) Intravenous and endobronchial administration of G4120, a cyclic Arg-Gly-Asp-containing platelet GPIIb/IIIa receptor-blocking pentapeptide, enhances and sustains coronary arterial thrombolysis with rt-PA in a canine preparation. Arterioscler Thromb, 13 (5): 738-47. [PMID:8485125]

36. Zhong M, Gadek TR, Bui M, Shen W, Burnier J, Barr KJ, Hanan EJ, Oslob JD, Yu CH, Zhu J et al.. (2012) Discovery and Development of Potent LFA-1/ICAM-1 Antagonist SAR 1118 as an Ophthalmic Solution for Treating Dry Eye. ACS Med Chem Lett, 3 (3): 203-6. [PMID:24900456]

Richard W. Farndale Division of Cardiovascular Medicine ACCI, Level 6, Box 110 Addenbrooke's Hospital Hills Road, Cambridge CB2 0QQ UK Gavin E. Jarvis School of Medicine, University of Sunderland City Campus Sciences Complex, Dale 001 Chester Road Sunderland, SR1 3SD UK