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{{Short description| | {{Short description|Transmembrane receptors involved in cellular adhesion and signalling}} | ||
{{stack| | {{stack| | ||
{{Infobox protein family | {{Infobox protein family | ||
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'''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). | '''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 | Several types of integrins exist, and one cell generally has multiple different types on its surface. Integrins are found in all [[animal cells]] while [[integrin-like receptors]] are found in [[plant cell]]s.<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]]. | 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]]. | ||
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== Function == | == 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 | | 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. | 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. | ||
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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> | 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 | | 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 nm and spaced at approximately 45 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> | 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> | ||