View source for Integrin

{{Short description|Instance of a defined set in Homo sapiens with Reactome ID (R-HSA-374573)}}
{{stack|
{{Infobox protein family
| Symbol = Integrin_alphaVbeta3
| Name = Integrin alphaVbeta3 extracellular domains
| image = PDB 1jv2 EBI.jpg
| width =
| caption = Structure of the extracellular segment of integrin alpha Vbeta3.<ref name="pmid11546839">{{cite journal | vauthors = Xiong JP, Stehle T, Diefenbach B, Zhang R, Dunker R, Scott DL, Joachimiak A, Goodman SL, Arnaout MA | title = Crystal structure of the extracellular segment of integrin alpha Vbeta3 | journal = Science | volume = 294 | issue = 5541 | pages = 339–45 | date = October 2001 | pmid = 11546839 | pmc = 2885948 | doi = 10.1126/science.1064535 | bibcode = 2001Sci...294..339X }}</ref>
| Pfam = PF08441
| Pfam_clan = CL0159
| InterPro = IPR013649
| SMART =
| PROSITE =
| SCOP = 1jv2
| TCDB =
| OPM family = 176
| OPM protein = 2knc
| PDB = 
| Membranome superfamily = 13
}}
{{Infobox protein family
| Symbol = Integrin_alpha
| Name = Integrin alpha cytoplasmic region
| image = PDB 1dpk EBI.jpg
| width =
| caption = Structure of chaperone protein PAPD.<ref name="pmid10446050">{{cite journal | vauthors = Sauer FG, Fütterer K, Pinkner JS, Dodson KW, Hultgren SJ, Waksman G | title = Structural basis of chaperone function and pilus biogenesis | journal = Science | volume = 285 | issue = 5430 | pages = 1058–61 | date = August 1999 | pmid = 10446050 | doi = 10.1126/science.285.5430.1058 }}</ref>
| Pfam = PF00357
| InterPro = IPR000413
| SMART =
| PROSITE = PDOC00215
| SCOP = 1dpk
| TCDB =
| OPM family = 
| OPM protein =
| PDB = 
}}
{{Infobox protein family
| Symbol = Integrin_beta
| Name = Integrin, beta chain (vWA)
| image =Integrinalpha.png
| width =
| caption =
| Pfam = PF00362
| InterPro = IPR002369
| SMART = SM00187
| PROSITE = PDOC00216
| SCOP = 1jv2
| TCDB =
| OPM family =
| OPM protein =
| PDB = {{PDB2|1jv2}}, {{PDB2|1kup}}, {{PDB2|1kuz}}, {{PDB2|1l3y}}, {{PDB2|1l5g}}, {{PDB2|1m1x}}, {{PDB2|1m8o}}, {{PDB2|1s4x}}, {{PDB2|1txv}}, {{PDB2|1ty3}}, {{PDB2|1ty5}}, {{PDB2|1ty6}}, {{PDB2|1ty7}}, {{PDB2|1tye}}, {{PDB2|1u8c}}
}}
{{Infobox protein family
| Symbol = Integrin_b_cyt
| Name = Integrin beta 7 cytoplasmic domain: complex with filamin
| image = PDB 2brq EBI.jpg
| width = 
| caption = crystal structure of the filamin a repeat 21 complexed with the integrin beta7 cytoplasmic tail peptide
| Pfam = PF08725
| Pfam_clan =  
| InterPro = IPR014836
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 1m8O
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}}}
'''Integrins''' are [[transmembrane receptors]] that help cell–cell and cell–[[extracellular matrix]] (ECM) adhesion.<ref name="pmid12297042">{{cite journal | vauthors = Hynes RO | title = Integrins: bidirectional, allosteric signaling machines | journal = Cell | volume = 110 | issue = 6 | pages = 673–87 | date = September 2002 | pmid = 12297042 | doi = 10.1016/s0092-8674(02)00971-6 | s2cid = 30326350 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Giancotti FG, Ruoslahti E | title = Integrin signaling | journal = Science | volume = 285 | issue = 5430 | pages = 1028–32 | date = August 1999 | pmid = 10446041 | doi = 10.1126/science.285.5430.1028 }}</ref> The presence of integrins allows rapid and flexible responses to events at the cell surface (''e.g''. signal [[platelet]]s to initiate an interaction with [[coagulation]] factors).

Several types of integrins exist, and one cell generally has multiple different types on its surface. Integrins are found in all animals while [[integrin-like receptors]] are found in plant cells.<ref name="pmid12297042"/>

Integrins work alongside other proteins such as [[cadherin]]s, the [[immunoglobulin superfamily]] [[cell adhesion molecule]]s, [[selectin]]s and [[syndecan]]s, to mediate cell–cell and cell–matrix interaction. [[Ligands]] for integrins include [[fibronectin]], [[vitronectin]], [[collagen]] and [[laminin]].

== Structure ==
Integrins are obligate [[Heteromer|heterodimers]] composed of α and β [[Protein subunit|subunits]].  Several genes code for multiple [[Protein isoform|isoforms]] of these subunits, which gives rise to an array of unique integrins with varied activity.  In mammals, integrins are assembled from eighteen α and eight β subunits,<ref>{{cite book | title = Molecular Biology of the Cell | edition = 4th | year = 2002 | publisher = Garland Science | location = New York | chapter = Integrins | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK26867/ | vauthors = Bruce A, Johnson A, Lewis J, Raff M, Roberts K, Walter P }}</ref> in ''[[Drosophila]]'' five α and two β subunits, and in ''[[Caenorhabditis]]'' nematodes two α subunits and one β subunit.<ref name=hump>{{cite journal | vauthors = Humphries MJ | title = Integrin structure | journal = Biochemical Society Transactions | volume = 28 | issue = 4 | pages = 311–39 | year = 2000 | pmid = 10961914 | doi = 10.1042/0300-5127:0280311 }}</ref> The α and β subunits are both class I transmembrane proteins, so each penetrates the plasma membrane once, and can possess several [[cytoplasm]]ic domains.<ref name="pmid2977331">{{cite journal | vauthors = Nermut MV, Green NM, Eason P, Yamada SS, Yamada KM | title = Electron microscopy and structural model of human fibronectin receptor | journal = The EMBO Journal | volume = 7 | issue = 13 | pages = 4093–9 | date = December 1988 | pmid = 2977331 | pmc = 455118 | doi =  10.1002/j.1460-2075.1988.tb03303.x}}</ref>

{| class="wikitable" style="text-align:center; float:left; margin-right:1em;"
|+ alpha {{nobold|(mammal)}}
|-
! gene
! protein
! synonyms
|-
| {{gene|ITGA1}}
| [[CD49a]]
| VLA1
|-
| {{gene|ITGA2}}
| [[CD49b]]
| VLA2
|-
| {{gene|ITGA3}}
| [[CD49c]]
| VLA3
|-
| {{gene|ITGA4}}
| [[CD49d]]
| VLA4
|-
| {{gene|ITGA5}}
| [[CD49e]]
| VLA5
|-
| {{gene|ITGA6}}
| [[ITGA6|CD49f]]
| VLA6
|-
| {{gene|ITGA7}}
| [[ITGA7]]
| FLJ25220
|-
| {{gene|ITGA8}}
| [[ITGA8]]
|
|-
| {{gene|ITGA9}}
| [[ITGA9]]
| RLC
|-
| {{gene|ITGA10}}
| [[ITGA10]]
| PRO827
|-
| {{gene|ITGA11}}
| [[ITGA11]]
| HsT18964
|-
| {{gene|ITGAD}}
| [[ITGAD|CD11D]]
| FLJ39841
|-
| {{gene|ITGAE}}
| [[ITGAE|CD103]]
| HUMINAE
|-
| {{gene|ITGAL}}
| [[CD11a]]
| LFA1A
|-
| {{gene|ITGAM}}
| [[Integrin alpha M|CD11b]]
| MAC-1
|-
| {{gene|ITGAV}}
| [[ITGAV|CD51]]
| VNRA, MSK8
|-
| {{gene|ITGA2B}}
| [[ITGA2B|CD41]]
| GPIIb
|-
| {{gene|ITGAX}}
| [[CD11c]]
|
|}

{| class="wikitable" style="text-align:center; float:left; margin-right:1em;"
|+ beta {{nobold|(mammal)}}
|-
! gene
! protein
! synonyms
|-
| {{Gene|ITGB1}}
| [[CD29]]
| FNRB, MSK12, MDF2
|-
| {{Gene|ITGB2}}
| [[CD18]]
| LFA-1, MAC-1, MFI7
|-
| {{Gene|ITGB3}}
| [[CD61]]
| GP3A, GPIIIa
|-
| {{Gene|ITGB4}}
| [[ITGB4|CD104]]
|
|-
| {{Gene|ITGB5}}
| [[Integrin, beta 5|ITGB5]]
| FLJ26658
|-
| {{Gene|ITGB6}}
| [[Integrin, beta 6|ITGB6]]
|
|-
| {{Gene|ITGB7}}
| [[ITGB7]]
|
|-
| {{Gene|ITGB8}}
| [[ITGB8]]
|
|}{{clear left}}

Variants of some subunits are formed by differential [[RNA splicing]]; for example, four variants of the beta-1 subunit exist. Through different combinations of the α and β subunits, 24 unique mammalian integrins are generated, excluding splice- and glycosylation variants.<ref name="hynes1">{{cite journal | vauthors = Hynes RO | title = Integrins: bidirectional, allosteric signaling machines | journal = Cell | volume = 110 | issue = 6 | pages = 673–87 | date = September 2002 | pmid = 12297042 | doi = 10.1016/S0092-8674(02)00971-6 | s2cid = 30326350 | doi-access = free }}</ref>

Integrin subunits span the [[cell membrane]] and have short cytoplasmic domains of 40–70 amino acids. The exception is the beta-4 subunit, which has a cytoplasmic domain of 1,088 amino acids, one of the largest of any membrane protein. Outside the cell membrane, the α and β chains lie close together along a length of about 23&nbsp;[[nanometre|nm]]; the final 5&nbsp;nm [[N-terminus|N-termini]] of each chain forms a [[ligand (biochemistry)|ligand-binding]] region for the ECM. They have been compared to [[lobster]] claws, although they don't actually "pinch" their ligand, they  chemically interact with it at the insides of the "tips" of their "pinchers".

The [[molecular mass]] of the integrin subunits can vary from {{val|90|ul=kDa}} to {{val|160|u=kDa}}. Beta subunits have four [[cysteine]]-rich repeated sequences. Both α and β subunits bind several [[divalent]] [[cation]]s. The role of divalent cations in the α subunit is unknown, but may stabilize the folds of the protein. The [[Ion|cations]] in the β subunits are more interesting: they are directly involved in coordinating at least some of the [[ligand (biochemistry)|ligands]] that integrins bind.

Integrins can be categorized in multiple ways. For example, some α chains have an additional structural element (or "domain") inserted toward the [[N-terminal]], the alpha-A domain (so called because it has a similar structure to the A-domains found in the protein [[von Willebrand factor]]; it is also termed the α-I domain). Integrins carrying this domain either bind to [[collagen]]s (e.g. integrins α1 β1, and α2 β1), or act as [[Cell–cell interaction|cell-cell]] adhesion molecules (integrins of the β2 family). This α-I domain is the binding site for ligands of such integrins. Those integrins that don't carry this inserted domain also have an A-domain in their ligand binding site, but ''this'' A-domain is found on the β subunit.

In both cases, the A-domains carry up to three divalent cation binding sites. One is permanently occupied in physiological [[concentration]]s of divalent cations, and carries either a calcium or magnesium ion, the principal divalent cations in blood at median concentrations of 1.4&nbsp;mM (calcium) and 0.8&nbsp;mM (magnesium). The other two sites become occupied by cations when ligands bind—at least for those ligands involving an acidic amino acid in their interaction sites. An acidic amino acid features in the integrin-interaction site of many ECM proteins, for example as part of the amino acid sequence [[Arginine-Glycine-Aspartic acid]] ("RGD" in the one-letter amino acid code).

=== Structure ===
Despite many years of effort, discovering the high-resolution structure of integrins proved to be challenging, as membrane proteins are classically difficult to purify, and as integrins are large, complex and highly [[glycosylation|glycosylated]] with many sugar 'trees' attached to them. Low-resolution images of detergent extracts of intact integrin GPIIbIIIa, obtained using [[electron microscopy]], and even data from indirect techniques that investigate the solution properties of integrins using [[ultracentrifugation]] and light scattering, were combined with fragmentary high-resolution crystallographic or NMR data from single or paired domains of single integrin chains, and molecular models postulated for the rest of the chains.

The [[X-ray]] crystal structure obtained for the complete extracellular region of one integrin, αvβ3,<ref name="pmid11546839"/> shows the molecule to be folded into an inverted V-shape that potentially brings the ligand-binding sites close to the cell membrane. Perhaps more importantly, the crystal structure was also obtained for the same integrin bound to a small ligand containing the RGD-sequence, the drug [[cilengitide]].<ref>{{cite journal | vauthors = Smith JW | title = Cilengitide Merck | journal = Current Opinion in Investigational Drugs | volume = 4 | issue = 6 | pages = 741–5 | date = June 2003 | pmid = 12901235 }}</ref> As detailed above, this finally revealed why divalent cations (in the A-domains) are critical for RGD-ligand binding to integrins. The interaction of such sequences with integrins is believed to be a primary switch by which ECM exerts its effects on cell behaviour.

The structure poses many questions, especially regarding ligand binding and signal transduction. The ligand binding site is directed towards the C-terminal of the integrin, the region where the molecule emerges from the cell membrane. If it emerges [[orthogonality|orthogonally]] from the membrane, the ligand binding site would apparently be obstructed, especially as integrin ligands are typically massive and well cross-linked components of the ECM. In fact, little is known about the angle that membrane proteins subtend to the plane of the membrane; this is a problem difficult to address with available technologies. The default assumption is that they emerge rather like little lollipops, but there is little evidence for this. The integrin structure has drawn attention to this problem, which may have general implications for how membrane proteins work. It appears that the integrin transmembrane helices are tilted (see "Activation" below), which hints that the extracellular chains may also not be orthogonal with respect to the membrane surface.

Although the crystal structure changed surprisingly little after binding to cilengitide, the current hypothesis is that integrin function involves changes in shape to move the ligand-binding site into a more accessible position, away from the cell surface, and this shape change also triggers intracellular signaling. There is a wide body of cell-biological and biochemical literature that supports this view. Perhaps the most convincing evidence involves the use of [[antibody|antibodies]] that only recognize integrins when they have bound to their ligands, or are activated. As the "footprint" that an antibody makes on its binding target is roughly a circle about 3&nbsp;nm in diameter, the resolution of this technique is low. Nevertheless, these so-called LIBS (Ligand-Induced-Binding-Sites) antibodies unequivocally show that dramatic changes in integrin shape routinely occur. However, how the changes detected with antibodies look on the structure is still unknown.

=== Activation ===

When released into the cell membrane, newly synthesized integrin dimers are speculated to be found in the same "bent" conformation revealed by the structural studies described above.  One school of thought claims that this bent form prevents them from interacting with their ligands, although bent forms can predominate in high-resolution EM structures of integrin bound to an ECM ligand. Therefore, at least in biochemical experiments, integrin dimers must apparently not be 'unbent' in order to prime them and allow their binding to the [[Extracellular matrix|ECM]]. In cells, the priming  is accomplished by a protein talin, which binds to the β tail of the integrin dimer and changes its conformation.<ref name="pmid15157154">{{cite journal | vauthors = Calderwood DA | title = Talin controls integrin activation | journal = Biochemical Society Transactions | volume = 32 | issue = Pt3 | pages = 434–7 | date = June 2004 | pmid = 15157154 | doi = 10.1042/BST0320434 }}</ref><ref name="pmid10497155">{{cite journal | vauthors = Calderwood DA, Zent R, Grant R, Rees DJ, Hynes RO, Ginsberg MH | title = The Talin head domain binds to integrin beta subunit cytoplasmic tails and regulates integrin activation | journal = The Journal of Biological Chemistry | volume = 274 | issue = 40 | pages = 28071–4 | date = October 1999 | pmid = 10497155 | doi = 10.1074/jbc.274.40.28071 | doi-access = free }}</ref> The α and β integrin chains are both class-I transmembrane proteins: they pass the plasma membrane as single transmembrane alpha-helices. Unfortunately, the helices are too long, and recent studies suggest that, for integrin gpIIbIIIa, they are tilted with respect both to one another and to the plane of the membrane. Talin binding alters the angle of tilt of the β3 chain transmembrane helix in model systems and this may reflect a stage in the process of inside-out signalling which primes integrins.<ref name="PMID20308986">{{cite journal | vauthors = Shattil SJ, Kim C, Ginsberg MH | title = The final steps of integrin activation: the end game | journal = Nature Reviews. Molecular Cell Biology | volume = 11 | issue = 4 | pages = 288–300 | date = April 2010 | pmid = 20308986 | pmc = 3929966 | doi = 10.1038/nrm2871 }}</ref> Moreover, talin proteins are able to dimerize<ref name="pmid8031639">{{cite journal | vauthors = Goldmann WH, Bremer A, Häner M, Aebi U, Isenberg G | title = Native talin is a dumbbell-shaped homodimer when it interacts with actin | journal = Journal of Structural Biology | volume = 112 | issue = 1 | pages = 3–10 | year = 1994 | pmid = 8031639 | doi = 10.1006/jsbi.1994.1002 }}</ref> and thus are thought to intervene in the clustering of integrin dimers which leads to the formation of a [[focal adhesion]]. Recently, the [[Kindlin-1]] and [[Kindlin-2]] proteins have also been found to interact with integrin and activate it.<ref name="pmid19240021">{{cite journal | vauthors = Harburger DS, Bouaouina M, Calderwood DA | title = Kindlin-1 and -2 directly bind the C-terminal region of beta integrin cytoplasmic tails and exert integrin-specific activation effects | journal = The Journal of Biological Chemistry | volume = 284 | issue = 17 | pages = 11485–97 | date = April 2009 | pmid = 19240021 | pmc = 2670154 | doi = 10.1074/jbc.M809233200 | doi-access = free }}</ref>

== Function ==
Integrins have two main functions, attachment of the cells to the ECM and signal transduction from the ECM to the cells.<ref>{{cite journal | vauthors = Yamada KM, Miyamoto S | title = Integrin transmembrane signaling and cytoskeletal control | journal = Current Opinion in Cell Biology | volume = 7 | issue = 5 | pages = 681–9 | date = October 1995 | pmid = 8573343 | doi = 10.1016/0955-0674(95)80110-3 }}</ref> They are also involved in a wide range of other biological activities, including extravasation, cell-to-cell adhesion, cell migration, and as receptors for certain viruses, such as [[adenovirus]], [[echovirus]], [[hantavirus]], [[foot-and-mouth disease]], [[polio virus]] and other viruses. Recently, the importance of integrins in the progress of autoimmune disorders is also gaining attention of the scientists. These mechanoreceptors seem to regulate autoimmunity by dictating various intracellular pathways to control immune cell adhesion to endothelial cell layers followed by their trans-migration. This process might or might not be dependent on the sheer force faced by the extracellular parts of different integrins.<ref>{{cite journal |last1=Banerjee |first1=S |last2=Nara |first2=R |last3=Chakraborty |first3=S |last4=Chowdhury |first4=D |last5=Haldar |first5=S |title=Integrin Regulated Autoimmune Disorders: Understanding the Role of Mechanical Force in Autoimmunity. |journal=Frontiers in Cell and Developmental Biology |date=2022 |volume=10 |article-number=852878 |doi=10.3389/fcell.2022.852878 |pmid=35372360 |pmc=8971850 |doi-access=free }}</ref>

A prominent function of the integrins is seen in the molecule [[Glycoprotein IIb/IIIa|GpIIb/IIIa]], an integrin on the surface of blood [[platelet]]s (thrombocytes) responsible for attachment to fibrin within a developing blood clot. This molecule dramatically increases its binding affinity for fibrin/fibrinogen through association of platelets with exposed collagens in the wound site. Upon association of platelets with collagen, GPIIb/IIIa changes shape, allowing it to bind to fibrin and other blood components to form the clot matrix and stop blood loss.

=== Attachment of cell to the ECM ===
Integrins couple the cell-[[extracellular matrix]] (ECM) outside a cell to the [[cytoskeleton]] (in particular, the [[microfilament]]s) inside the cell. Which ligand in the ECM the integrin can bind to is defined by which α and β subunits the integrin is made of. Among the [[ligand]]s of integrins are [[fibronectin]], [[vitronectin]], [[collagen]], and [[laminin]]. The connection between the cell and the ECM may help the cell to endure pulling forces without being ripped out of the ECM. The ability of a cell to create this kind of bond is also of vital importance in [[ontogeny]].

Cell attachment to the ECM is a basic requirement to build a multicellular organism. Integrins are not simply hooks, but give the cell critical signals about the nature of its surroundings. Together with signals arising from receptors for soluble growth factors like [[Vascular endothelial growth factor|VEGF]], [[epidermal growth factor|EGF]], and many others, they enforce a cellular decision on what biological action to take, be it attachment, movement, death, or differentiation. Thus integrins lie at the heart of many cellular biological processes. The attachment of the cell takes place through formation of [[cell adhesion]] complexes, which consist of integrins and many cytoplasmic proteins, such as [[talin (protein)|talin]], [[vinculin]], [[paxillin]], and alpha-[[actinin]]. These act by regulating [[kinase]]s such as FAK ([[focal adhesion kinase]]) and [[Src kinase]] family members to phosphorylate substrates such as p130CAS thereby recruiting signaling adaptors such as [[CRK (gene)|CRK]]. These adhesion complexes attach to the actin cytoskeleton. The integrins thus serve to link two networks across the plasma membrane: the extracellular ECM and the intracellular actin filamentous system. Integrin α6β4 is an exception: it links to the keratin intermediate filament system in epithelial cells.<ref name="pmid16581764">{{cite journal | vauthors = Wilhelmsen K, Litjens SH, Sonnenberg A | title = Multiple functions of the integrin alpha6beta4 in epidermal homeostasis and tumorigenesis | journal = Molecular and Cellular Biology | volume = 26 | issue = 8 | pages = 2877–86 | date = April 2006 | pmid = 16581764 | pmc = 1446957 | doi = 10.1128/MCB.26.8.2877-2886.2006 }}</ref>

Focal adhesions are large molecular complexes, which are generated following interaction of integrins with ECM, then their clustering.  The clusters likely provide sufficient intracellular binding sites to permit the formation of stable signaling complexes on the cytoplasmic side of the cell membrane. So the focal adhesions contain integrin ligand, integrin molecule, and associate plaque proteins. Binding is propelled by changes in free energy.<ref name="pmid20805876">{{cite journal | vauthors = Olberding JE, Thouless MD, [[Ellen Arruda|Arruda EM]], Garikipati K | title = The non-equilibrium thermodynamics and kinetics of focal adhesion dynamics | journal = PLOS ONE | volume = 5 | issue = 8 | article-number = e12043 | date = August 2010 | pmid = 20805876 | pmc = 2923603 | doi = 10.1371/journal.pone.0012043 | veditors = Buehler MJ | bibcode = 2010PLoSO...512043O | doi-access = free }}</ref> As previously stated, these complexes  connect the extracellular matrix to actin bundles. Cryo-electron tomography reveals that the adhesion contains particles on the cell membrane with diameter of 25 +/- 5&nbsp;nm and spaced at approximately 45&nbsp;nm.<ref name="pmid20694000">{{cite journal | vauthors = Patla I, Volberg T, Elad N, Hirschfeld-Warneken V, Grashoff C, Fässler R, Spatz JP, Geiger B, Medalia O | title = Dissecting the molecular architecture of integrin adhesion sites by cryo-electron tomography | journal = Nature Cell Biology | volume = 12 | issue = 9 | pages = 909–15 | date = September 2010 | pmid = 20694000 | doi = 10.1038/ncb2095 | s2cid = 20775305 }}</ref> Treatment with Rho-kinase inhibitor [[Y-27632]] reduces the size of the particle, and it is extremely mechanosensitive.<ref name="urlMechanosensitive channels">{{cite web| url =http://www.ks.uiuc.edu/Research/MscLchannel/| title =Mechanosensitive channels| vauthors =Gullingsrud J, Sotomayor M| publisher =Theoretical and Computational Biophysics Group, Beckman Institute for Advanced Science and Technology: University of Illinois at Urbana-Champaign| url-status =live| archive-url =https://web.archive.org/web/20101202060530/http://www.ks.uiuc.edu/Research/MscLchannel/| archive-date =2010-12-02}}</ref>

One important function of integrins on cells in tissue culture is their role in [[cell migration]]. Cells adhere to a [[substrate (biology)|substrate]] through their integrins. During movement, the cell makes new attachments to the substrate at its front and concurrently releases those at its rear. When released from the substrate, integrin molecules are taken back into the cell by [[endocytosis]]; they are transported through the cell to its front by the [[endocytic cycle]], where they are added back to the surface. In this way they are cycled for reuse, enabling the cell to make fresh attachments at its leading front.<ref>{{cite journal | vauthors = Paul NR, Jacquemet G, Caswell PT | title = Endocytic Trafficking of Integrins in Cell Migration | language = en | journal = Current Biology | volume = 25 | issue = 22 | pages = R1092-105 | date = November 2015 | pmid = 26583903 | doi = 10.1016/j.cub.2015.09.049 | doi-access = free }}</ref> The cycle of integrin endocytosis and recycling back to the cell surface is important for migrating cells and also during animal development.<ref>{{cite journal | vauthors = Moreno-Layseca P, Icha J, Hamidi H, Ivaska J | title = Integrin trafficking in cells and tissues | journal = Nature Cell Biology | volume = 21 | issue = 2 | pages = 122–132 | date = February 2019 | pmid = 30602723 | pmc = 6597357 | doi = 10.1038/s41556-018-0223-z }}</ref>

=== Signal transduction ===
Integrins play an important role in cell signaling by modulating the cell signaling pathways of transmembrane protein kinases such as receptor tyrosine kinases (RTK). While the interaction between integrin and receptor tyrosine kinases originally  was thought of as uni-directional and supportive, recent studies indicate that integrins have additional, multi-faceted roles in cell signaling. 
Integrins can regulate the receptor tyrosine kinase signaling by recruiting specific adaptors to the plasma membrane. For example, β1c integrin recruits Gab1/Shp2 and presents Shp2 to IGF1R, resulting in dephosphorylation of the receptor.<ref>{{cite journal | vauthors = Goel HL, Breen M, Zhang J, Das I, Aznavoorian-Cheshire S, Greenberg NM, Elgavish A, Languino LR | title = beta1A integrin expression is required for type 1 insulin-like growth factor receptor mitogenic and transforming activities and localization to focal contacts | journal = Cancer Research | volume = 65 | issue = 15 | pages = 6692–700 | date = August 2005 | pmid = 16061650 | doi = 10.1158/0008-5472.CAN-04-4315 | doi-access =  }}</ref>  In a reverse direction, when a receptor tyrosine kinase is activated, integrins co-localise at focal adhesion with the receptor tyrosine kinases and their associated signaling molecules.

The repertoire of integrins expressed on a particular cell can specify the signaling pathway due to the differential binding affinity of ECM ligands for the integrins. The tissue stiffness and matrix composition can initiate specific signaling pathways regulating cell behavior. Clustering and activation of the integrins/actin complexes strengthen the focal adhesion interaction and initiate the framework for cell signaling through assembly of adhesomes.<ref name="pmid21307119">{{cite journal | vauthors = Kim SH, Turnbull J, Guimond S | title = Extracellular matrix and cell signalling: the dynamic cooperation of integrin, proteoglycan and growth factor receptor | journal = The Journal of Endocrinology | volume = 209 | issue = 2 | pages = 139–51 | date = May 2011 | pmid = 21307119 | doi = 10.1530/JOE-10-0377 | doi-access =  }}</ref>

Depending on the integrin's regulatory impact on specific receptor tyrosine kinases, the cell can experience:
* [[cell growth]]<ref name=":0">{{cite book | vauthors = Bostwick DG, Cheng L | chapter = 9 - Neoplasms of the Prostate|date=2020-01-01 | title = Urologic Surgical Pathology | edition = Fourth |pages=415–525.e42| veditors = Cheng L, MacLennan GT, Bostwick DG |place=Philadelphia|publisher=Content Repository Only!|language=en|isbn=978-0-323-54941-7 }}</ref>
* [[cell division]]<ref name=":0" />
* cell survival<ref name=":0" />
* [[cellular differentiation]]
* [[apoptosis|apoptosis (programmed cell death)]]

Knowledge of the relationship between integrins and receptor tyrosine kinase has laid a foundation for new approaches to cancer therapy. Specifically, targeting integrins associated with RTKs is an emerging approach for inhibiting angiogenesis.<ref>{{cite journal | vauthors = Carbonell WS, DeLay M, Jahangiri A, Park CC, Aghi MK | title = β1 integrin targeting potentiates antiangiogenic therapy and inhibits the growth of bevacizumab-resistant glioblastoma | journal = Cancer Research | volume = 73 | issue = 10 | pages = 3145–54 | date = May 2013 | pmid = 23644530 | pmc = 4040366 | doi = 10.1158/0008-5472.CAN-13-0011 }}</ref>

[[File:Figure 1 - Nieuwenhuis et al 2018 - Integrins promote axonal regeneration after injury of the nervous system - Biological Reviews - doi 10.1111-brv.12398.jpg|thumb|Integrins are localised at the growth cone of regenerating neurons.<ref name="Nieuwenhuis2018a" />]]

== Integrins and nerve repair ==
Integrins have an important function in [[neuroregeneration]] after injury of the [[peripheral nervous system]] (PNS).<ref name="Nieuwenhuis2018a">{{cite journal | vauthors = Nieuwenhuis B, Haenzi B, Andrews MR, Verhaagen J, Fawcett JW | title = Integrins promote axonal regeneration after injury of the nervous system | journal = Biological Reviews of the Cambridge Philosophical Society | volume =  93| issue =  3| pages = 1339–1362 | date = February 2018 | pmid = 29446228 | pmc = 6055631 | doi = 10.1111/brv.12398 }}</ref> Integrins are present at the [[growth cone]] of damaged PNS neurons and attach to ligands in the ECM to promote axon regeneration. It is unclear whether integrins can promote axon regeneration in the adult [[central nervous system]] (CNS). There are two obstacles that prevent integrin-mediated regeneration in the CNS: 1) integrins are not localised in the axon of most adult CNS neurons and 2) integrins become inactivated by molecules in the scar tissue after injury.<ref name=Nieuwenhuis2018a/>

== Vertebrate integrins ==
The following are 16 of the ~24 integrins found in vertebrates:
{| class="wikitable"
! Name !! Synonyms !! Distribution !! Ligands
 |-
 | '''α<sub>1</sub>β<sub>1</sub>'''  ||VLA-1 ||  Many  || [[Collagen]]s, [[laminin]]s<ref name="lodish">{{cite book | vauthors = Krieger M, Scott MP, Matsudaira PT, Lodish HF, Darnell JE, Zipursky L, Kaiser C, Berk A | title = Molecular cell biology | edition = fifth | publisher = W.H. Freeman and CO | location = New York | year = 2004 | isbn = 978-0-7167-4366-8 | url = https://archive.org/details/molecularcellbio00harv | url-access = registration }}</ref>
 |-
 | '''α<sub>2</sub>β<sub>1</sub>'''  || VLA-2||  Many  || Collagens, laminins<ref name=lodish/>
 |-
 | '''α<sub>3</sub>β<sub>1</sub>'''  || VLA-3||  Many  || Laminin-5 
 |-
 | '''[[VLA-4|α<sub>4</sub>β<sub>1</sub>]]'''  || VLA-4<ref name=lodish/> ||  [[Hematopoietic]] cells  ||  [[Fibronectin]], [[VCAM-1]]<ref name=lodish/>
 |-
 | '''[[LPAM-1|α<sub>4</sub>β<sub>7</sub>]]'''|| LPAM-1|| T cells ||  MAD-CAM1<ref>{{Cite journal |last1=Wang |first1=Caihong |last2=McDonough |first2=Jacquelyn S. |last3=McDonald |first3=Keely G. |last4=Huang |first4=Conway |last5=Newberry |first5=Rodney D. |date=2008-09-15 |title=Alpha4beta7/MAdCAM-1 interactions play an essential role in transitioning cryptopatches into isolated lymphoid follicles and a nonessential role in cryptopatch formation |journal=Journal of Immunology |volume=181 |issue=6 |pages=4052–4061 |doi=10.4049/jimmunol.181.6.4052 |issn=1550-6606 |pmc=2778276 |pmid=18768861}}</ref><ref>{{Cite journal |last1=Wagner |first1=N. |last2=Löhler |first2=J. |last3=Kunkel |first3=E. J. |last4=Ley |first4=K. |last5=Leung |first5=E. |last6=Krissansen |first6=G. |last7=Rajewsky |first7=K. |last8=Müller |first8=W. |date=1996-07-25 |title=Critical role for beta7 integrins in formation of the gut-associated lymphoid tissue |journal=Nature |volume=382 |issue=6589 |pages=366–370 |doi=10.1038/382366a0 |issn=0028-0836 |pmid=8684468}}</ref>
|-
 | '''[[alpha-5 beta-1|α<sub>5</sub>β<sub>1</sub>]]'''|| VLA-5; fibronectin receptor || widespread || fibronectin<ref name="lodish" /> and [[proteinase]]s
 |-
 | '''[[alpha-6 beta-1|α<sub>6</sub>β<sub>1</sub>]]'''|| VLA-6; laminin receptor|| widespread || laminins
 |-
 | '''[[alpha-7 beta-1|α<sub>7</sub>β<sub>1</sub>]]'''|| ||  muscle, glioma  || laminins
 |-
 | '''[[LFA-1|α<sub>L</sub>β<sub>2</sub>]]'''|| LFA-1<ref name="lodish" />||  [[T-lymphocyte]]s||  [[ICAM-1]], [[ICAM-2]]<ref name="lodish" />
 |-
 | '''[[Integrin alpha M|α<sub>M</sub>β<sub>2</sub>]]'''|| Mac-1, CR3<ref name="lodish" />|| [[Neutrophil]]s and [[monocyte]]s||  [[Blood plasma|Serum]] proteins, ICAM-1<ref name="lodish" />
 |-
 | '''[[Glycoprotein IIb/IIIa|α<sub>IIb</sub>β<sub>3</sub>]]'''||  Fibrinogen receptor; gpIIbIIIa<ref name="pmid9150551">{{cite journal |vauthors=Elangbam CS, Qualls CW, Dahlgren RR |date=January 1997 |title=Cell adhesion molecules--update |journal=Veterinary Pathology |volume=34 |issue=1 |pages=61–73 |doi=10.1177/030098589703400113 |pmid=9150551 |doi-access=}}</ref>|| [[Platelet]]s<ref name="lodish" />||  fibrinogen, fibronectin<ref name="lodish" />
 |-
 | '''[[alpha-v beta-1|α<sub>V</sub>β<sub>1</sub>]]'''|| || neurological tumors||  [[vitronectin]], [[osteopontin]],<ref name="PMID17910028">{{cite journal |last1=Kazanecki |first1=CC |last2=Uzwiak |first2=DJ |last3=Denhxxardt |first3=DT |date=1 November 2007 |title=Control of osteopontin signaling and function by post-translational phosphorylation and protein folding. |journal=Journal of Cellular Biochemistry |volume=102 |issue=4 |pages=912–24 |doi=10.1002/jcb.21558 |pmid=17910028 |s2cid=24240459}}</ref> fibrinogen
 |-
 | '''[[alpha-v beta-3|α<sub>V</sub>β<sub>3</sub>]]'''||  vitronectin receptor<ref name="pmid10037797">{{cite journal |vauthors=Hermann P, Armant M, Brown E, Rubio M, Ishihara H, Ulrich D, Caspary RG, Lindberg FP, Armitage R, Maliszewski C, Delespesse G, Sarfati M |date=February 1999 |title=The vitronectin receptor and its associated CD47 molecule mediates proinflammatory cytokine synthesis in human monocytes by interaction with soluble CD23 |journal=The Journal of Cell Biology |volume=144 |issue=4 |pages=767–75 |doi=10.1083/jcb.144.4.767 |pmc=2132927 |pmid=10037797}}</ref>|| activated endothelial cells, melanoma, glioblastoma  ||  [[vitronectin]],<ref name="pmid10037797" /> fibronectin, fibrinogen, [[osteopontin]],<ref name="PMID17910028" /> [[CYR61|Cyr61]], [[thyroxine]],<ref>{{cite journal |vauthors=Bergh JJ, Lin HY, Lansing L, Mohamed SN, Davis FB, Mousa S, Davis PJ |date=July 2005 |title=Integrin alphaVbeta3 contains a cell surface receptor site for thyroid hormone that is linked to activation of mitogen-activated protein kinase and induction of angiogenesis |journal=Endocrinology |volume=146 |issue=7 |pages=2864–71 |doi=10.1210/en.2005-0102 |pmid=15802494 |doi-access=free}}</ref> [[TETRAC]]
 |-
 | '''[[alpha-v beta-5|α<sub>V</sub>β<sub>5</sub>]]'''|| || widespread, esp. fibroblasts, epithelial cells  ||  [[vitronectin]], osteopontin,<ref name="PMID17910028" /> and adenovirus
 |-
 | '''[[alpha-v beta-6|α<sub>V</sub>β<sub>6</sub>]]'''|| || proliferating epithelia, esp. lung and mammary gland  ||  [[fibronectin]]; [[TGFβ]]1+3
 |-
 | '''[[alpha-v beta-8|α<sub>V</sub>β<sub>8</sub>]]'''|| || neural tissue; peripheral nerve  || [[fibronectin]]; [[TGFβ]]1+3
|-
|'''α<sub>6</sub>β<sub>4</sub>'''
|
|[[Epithelial]] cells<ref name="lodish" />
|[[Laminin]]<ref name="lodish" />
|}

Beta-1 integrins interact with many alpha integrin chains. Gene knockouts of integrins in mice are not always lethal, which suggests that during embryonal development, one integrin may substitute its function for another in order to allow survival. Some integrins are on the cell surface in an inactive state, and can be rapidly primed, or put into a state capable of binding their ligands, by cytokines. Integrins can assume several different well-defined shapes or "conformational states". Once primed, the conformational state changes to stimulate ligand binding, which then activates the receptors — also by inducing a shape change — to trigger outside-in signal transduction.

== See also ==
* [[D-dimer]]
* [[Disintegrin]]
* [[Exopolymer]]
* [[Extracellular polymeric substance]] (EPS or XPS)

== References ==
{{Reflist}}

== External links ==
{{commons-inline|Category:Integrins|Integrins}}
* [https://www.youtube.com/watch?v=8DOTnKHFTTg Talin substrate for calpain] – PMAP [[The Proteolysis Map]] animation.
* {{MeshName|Integrins}}

{{Integrins}}
{{Cell adhesion molecules}}
{{Growth factor receptor modulators}}
{{Signal transduction}}

[[Category:Integrins| ]]
[[Category:Transmembrane proteins]]
[[Category:Cell adhesion proteins]]