{{Short description|Protein found in humans}} {{cs1 config|name-list-style=vanc}} {{Infobox_gene}} '''Cortactin''' (from "''<u>cort</u>ical <u>actin</u>'' binding protein") is a monomeric protein located in the cytoplasm of cells that can be activated by external stimuli to promote polymerization and rearrangement of the actin cytoskeleton, especially the actin cortex around the cellular periphery.<ref name="pmid16990456">{{cite journal | vauthors = Cosen-Binker LI, Kapus A | title = Cortactin: the gray eminence of the cytoskeleton | journal = Physiology | volume = 21 | issue = 5 | pages = 352–61 | date = October 2006 | pmid = 16990456 | doi = 10.1152/physiol.00012.2006 }}</ref><ref name="pmid18615630">{{cite journal | vauthors = Ammer AG, Weed SA | title = Cortactin branches out: roles in regulating protrusive actin dynamics | journal = Cell Motil. Cytoskeleton | volume = 65 | issue = 9 | pages = 687–707 | date = September 2008 | pmid = 18615630 | pmc = 2561250 | doi = 10.1002/cm.20296 }}</ref> It is present in all cell types. When activated, it will recruit Arp2/3 complex proteins to existing actin microfilaments, facilitating and stabilizing nucleation sites for actin branching. Cortactin is important in promoting lamellipodia formation, invadopodia formation, cell migration, and endocytosis.
== Gene == In humans, cortactin is encoded by the ''CTTN'' gene on chromosome 11.<ref name="pmid7685625">{{cite journal | vauthors = Brookes S, Lammie GA, Schuuring E, de Boer C, Michalides R, Dickson C, Peters G | title = Amplified region of chromosome band 11q13 in breast and squamous cell carcinomas encompasses three CpG islands telomeric of FGF3, including the expressed gene EMS1 | journal = Genes Chromosomes Cancer | volume = 6 | issue = 4 | pages = 222–31 | date = April 1993 | pmid = 7685625 | doi = 10.1002/gcc.2870060406 | s2cid = 36282099 }}</ref>
== Structure ==
Cortactin is a thin, elongated monomer that consists of an amino-terminal acidic (NTA) region; 37-residue-long segments that are highly conserved among cortactin proteins of all species and repeated up to 6.5 times in tandem (“cortactin repeats”); a proline-rich region; and an SH3 domain. This basic structure is highly conserved among all species that express cortactin.<ref name="Daly_2004">{{cite journal | vauthors = Daly RJ | title = Cortactin signalling and dynamic actin networks | journal = Biochem. J. | volume = 382 | issue = Pt 1 | pages = 13–25 | date = August 2004 | pmid = 15186216 | pmc = 1133910 | doi = 10.1042/BJ20040737 }}</ref>
== Activation and binding ==
Cortactin is activated via phosphorylation, by tyrosine kinases or serine/threonine kinases, in response to extracellular signals like growth factors, adhesion sites, or pathogenic invasion of the epithelial layer.
The SH3 domain of certain tyrosine kinases, such as the oncogene Src kinase, binds to cortactin's proline-rich region and phosphorylates it on Tyr421, Tyr466, and Tyr482. Once activated in this way, it can bind to filamentous actin (F-actin) with the fourth of its cortactin repeats.<ref name="Daly_2004"/> As the concentration of phosphorylated cortactin increases in specific regions within the cell, the monomers each begin to recruit an Arp2/3 complex to F-actin. It binds to Arp2/3 with an aspartic acid-aspartic acid-tryptophan (DDW) sequence in its NTA region, a motif that is often seen in other actin nucleation-promoting factors (NPFs).<ref name="Weed_2000">{{cite journal | vauthors = Weed SA, Karginov AV, Schafer DA, Weaver AM, Kinley AW, Cooper JA, Parsons JT | title = Cortactin localization to sites of actin assembly in lamellipodia requires interactions with F-actin and the Arp2/3 complex | journal = J. Cell Biol. | volume = 151 | issue = 1 | pages = 29–40 | date = October 2000 | pmid = 11018051 | pmc = 2189811 | doi = 10.1083/jcb.151.1.29 }}</ref>
Certain serine/threonine kinases, such as ERK, can phosphorylate cortactin on Ser405 and Ser418 in the SH3 domain.<ref name="Daly_2004"/> Activated like this, it still associates with Arp2/3 and F-actin, but will also allow other actin NPFs, most importantly N-WASp (Neuronal Wiskott-Aldrich syndrome protein), to bind to the complex as well; when phosphorylated by tyrosine kinases, other NPFs are excluded.<ref name="Martinez-Quiles_2004">{{cite journal | vauthors = Martinez-Quiles N, Ho HY, Kirschner MW, Ramesh N, Geha RS | title = Erk/Src phosphorylation of cortactin acts as a switch on-switch off mechanism that controls its ability to activate N-WASP | journal = Mol. Cell. Biol. | volume = 24 | issue = 12 | pages = 5269–80 | date = June 2004 | pmid = 15169891 | pmc = 419870 | doi = 10.1128/MCB.24.12.5269-5280.2004 }}</ref> The ability of these other NPFs to bind the Arp2/3 complex while cortactin is also bound could come from new interactions with cortactin's SH3 domain, which is in a different conformation when phosphorylated by Ser/Thr kinases and thus may be more open to interactions with other NPFs.<ref name="Martinez-Quiles_2004"/> Having other NPFs bind to the Arp2/3 complex at the same time as cortactin may enhance nucleation site stability.<ref name="Daly_2004"/>
== Location and function in the cell ==
Inactive cortactin diffuses throughout the cytoplasm, but upon phosphorylation, the protein begins to target certain areas in the cell. Cortactin-assisted Arp2/3-nucleated actin branches are most prominent in the actin cortex, around the periphery of the cell.<ref name="Weaver_2001">{{cite journal | vauthors = Weaver AM, Karginov AV, Kinley AW, Weed SA, Li Y, Parsons JT, Cooper JA | title = Cortactin promotes and stabilizes Arp2/3-induced actin filament network formation | journal = Curr. Biol. | volume = 11 | issue = 5 | pages = 370–4 | date = March 2001 | pmid = 11267876 | doi = 10.1016/S0960-9822(01)00098-7 | s2cid = 18931911 | doi-access = free | bibcode = 2001CBio...11..370W }}</ref> A phosphorylated cortactin monomer binds to, activates, and stabilizes an Arp2/3 complex on preexisting F-actin, which provides a nucleation site for a new actin branch to form from the “mother” filament. Branches formed from cortactin-assisted nucleation sites are very stable; cortactin has been shown to inhibit debranching.<ref name="Weaver_2001" /> Thus, polymerization and branching of actin is promoted in areas of the cell where cortactin is localized.
Cortactin is very active in lamellipodia, protrusions of the cell membrane formed by actin polymerization and treadmilling that propel the cell along a surface as it migrates towards some target.<ref name="Weed_2001">{{cite journal | vauthors = Weed SA, Parsons JT | title = Cortactin: coupling membrane dynamics to cortical actin assembly | journal = Oncogene | volume = 20 | issue = 44 | pages = 6418–34 | date = October 2001 | pmid = 11607842 | doi = 10.1038/sj.onc.1204783 | doi-access = free }}</ref>
Cortactin acts as a link between extracellular signals and lamellipodial “steering.” When a receptor tyrosine kinase on the cell membrane binds to an adhesion site, for example, cortactin will be phosphorylated locally to the area of binding, activate and recruit Arp2/3 to the actin cortex in that region, and thus stimulate cortical actin polymerization and movement of the cell in that direction. Macrophages, highly motile immune cells that engulf cellular debris and pathogens, are propelled by lamellipodia and identify/migrate toward a target via chemotaxis; thus, cortactin must also be activated by receptor kinases that pick up a large variety of chemical signals.<ref name="Weed_2001"/>
Studies have implicated cortactin in both clathrin-mediated endocytosis<ref name="Samaj_2004">{{cite journal | vauthors = Samaj J, Baluska F, Voigt B, Schlicht M, Volkmann D, Menzel D | title = Endocytosis, actin cytoskeleton, and signaling | journal = Plant Physiol. | volume = 135 | issue = 3 | pages = 1150–61 | date = July 2004 | pmid = 15266049 | pmc = 519036 | doi = 10.1104/pp.104.040683 }}</ref> and clathrin-independent endocytosis.<ref name="Sauvonnet_2005">{{cite journal | vauthors = Sauvonnet N, Dujeancourt A, Dautry-Varsat A | title = Cortactin and dynamin are required for the clathrin-independent endocytosis of gammac cytokine receptor | journal = J. Cell Biol. | volume = 168 | issue = 1 | pages = 155–63 | date = January 2005 | pmid = 15623579 | pmc = 2171671 | doi = 10.1083/jcb.200406174 }}</ref> In both kinds of endocytosis, it has long been known that actin localizes to sites of vesicle invagination and is a vital part of the endocytic pathway, but the actual mechanisms by which actin facilitates endocytosis are still unclear. Recently, however, it has been found that dynamin, the protein responsible for breaking the newly formed vesicular bud off the inside of the plasma membrane, can associate with the SH3 domain of cortactin. Since cortactin recruits the Arp2/3 complexes that lead to actin polymerization, this suggests that it may play an important part in linking vesicle formation to the as yet unknown functions actin has in endocytosis.<ref name="Zhu_2005">{{cite journal | vauthors = Zhu J, Zhou K, Hao JJ, Liu J, Smith N, Zhan X | title = Regulation of cortactin/dynamin interaction by actin polymerization during the fission of clathrin-coated pits | journal = J. Cell Sci. | volume = 118 | issue = Pt 4 | pages = 807–17 | date = February 2005 | pmid = 15671060 | doi = 10.1242/jcs.01668 | s2cid = 25923754 | url =https://zenodo.org/record/897807 | doi-access = free }}</ref>
== Clinical significance ==
Amplification of the genes encoding cortactin—in humans, EMS1—has been found to occur in certain tumors. Overexpression of cortactin can lead to highly-active lamellipodia in tumor cells, dubbed “invadopodia.” These cells are especially invasive and migratory, making them very dangerous, for they can easily spread cancer across the body into other tissues.<ref name="Weaver_2006">{{cite journal | vauthors = Weaver AM | title = Invadopodia: specialized cell structures for cancer invasion | journal = Clin. Exp. Metastasis | volume = 23 | issue = 2 | pages = 97–105 | year = 2006 | pmid = 16830222 | doi = 10.1007/s10585-006-9014-1 | s2cid = 41198210 }}</ref>
== Interactions ==
Cortactin has been shown to interact with: * ACTR3<ref name = pmid11018051/><ref name = pmid12176742>{{cite journal | vauthors = Di Ciano C, Nie Z, Szászi K, Lewis A, Uruno T, Zhan X, Rotstein OD, Mak A, Kapus A | title = Osmotic stress-induced remodeling of the cortical cytoskeleton | journal = Am. J. Physiol., Cell Physiol. | volume = 283 | issue = 3 | pages = C850-65 | date = September 2002 | pmid = 12176742 | doi = 10.1152/ajpcell.00018.2002 }}</ref> * ARPC2,<ref name = pmid11018051>{{cite journal | vauthors = Weed SA, Karginov AV, Schafer DA, Weaver AM, Kinley AW, Cooper JA, Parsons JT | title = Cortactin localization to sites of actin assembly in lamellipodia requires interactions with F-actin and the Arp2/3 complex | journal = J. Cell Biol. | volume = 151 | issue = 1 | pages = 29–40 | date = October 2000 | pmid = 11018051 | pmc = 2189811 | doi = 10.1083/jcb.151.1.29}}</ref> * CTNND1,<ref name = pmid12835311>{{cite journal | vauthors = Martinez MC, Ochiishi T, Majewski M, Kosik KS | title = Dual regulation of neuronal morphogenesis by a delta-catenin-cortactin complex and Rho | journal = J. Cell Biol. | volume = 162 | issue = 1 | pages = 99–111 | date = July 2003 | pmid = 12835311 | pmc = 2172717 | doi = 10.1083/jcb.200211025 }}</ref> * FER,<ref name = pmid9722593>{{cite journal | vauthors = Kim L, Wong TW | title = Growth factor-dependent phosphorylation of the actin-binding protein cortactin is mediated by the cytoplasmic tyrosine kinase FER | journal = J. Biol. Chem. | volume = 273 | issue = 36 | pages = 23542–8 | date = September 1998 | pmid = 9722593 | doi = 10.1074/jbc.273.36.23542| doi-access = free }}</ref> * KCNA2,<ref name = pmid12151401>{{cite journal | vauthors = Hattan D, Nesti E, Cachero TG, Morielli AD | title = Tyrosine phosphorylation of Kv1.2 modulates its interaction with the actin-binding protein cortactin | journal = J. Biol. Chem. | volume = 277 | issue = 41 | pages = 38596–606 | date = October 2002 | pmid = 12151401 | doi = 10.1074/jbc.M205005200 | doi-access = free }}</ref> * SHANK2,<ref name = pmid9742101>{{cite journal | vauthors = Du Y, Weed SA, Xiong WC, Marshall TD, Parsons JT | title = Identification of a novel cortactin SH3 domain-binding protein and its localization to growth cones of cultured neurons | journal = Mol. Cell. Biol. | volume = 18 | issue = 10 | pages = 5838–51 | date = October 1998 | pmid = 9742101 | pmc = 109170 | doi = 10.1128/MCB.18.10.5838}}</ref> * WASL,<ref name = pmid11830518>{{cite journal | vauthors = Mizutani K, Miki H, He H, Maruta H, Takenawa T | title = Essential role of neural Wiskott-Aldrich syndrome protein in podosome formation and degradation of extracellular matrix in src-transformed fibroblasts | journal = Cancer Res. | volume = 62 | issue = 3 | pages = 669–74 | date = February 2002 | pmid = 11830518 }}</ref> and * WIPF1.<ref name = pmid12620186>{{cite journal | vauthors = Kinley AW, Weed SA, Weaver AM, Karginov AV, Bissonette E, Cooper JA, Parsons JT | title = Cortactin interacts with WIP in regulating Arp2/3 activation and membrane protrusion | journal = Curr. Biol. | volume = 13 | issue = 5 | pages = 384–93 | date = March 2003 | pmid = 12620186 | doi = 10.1016/s0960-9822(03)00107-6| s2cid = 17357571 | doi-access = free | bibcode = 2003CBio...13..384K }}</ref>
== See also == * actin * gelsolin * transferrin * villin
== References == {{Reflist|35em}}
== Further reading == {{refbegin|35em}} * {{cite journal | vauthors = Weed SA, Parsons JT | title = Cortactin: coupling membrane dynamics to cortical actin assembly. | journal = Oncogene | volume = 20 | issue = 44 | pages = 6418–34 | year = 2001 | pmid = 11607842 | doi = 10.1038/sj.onc.1204783 | doi-access = free }} * {{cite journal | vauthors = Buday L, Downward J | title = Roles of cortactin in tumor pathogenesis. | journal = Biochim. Biophys. Acta | volume = 1775 | issue = 2 | pages = 263–73 | year = 2007 | pmid = 17292556 | doi = 10.1016/j.bbcan.2006.12.002 }} * {{cite journal | vauthors = Schuuring E, Verhoeven E, Mooi WJ, Michalides RJ | title = Identification and cloning of two overexpressed genes, U21B31/PRAD1 and EMS1, within the amplified chromosome 11q13 region in human carcinomas. | journal = Oncogene | volume = 7 | issue = 2 | pages = 355–61 | year = 1992 | pmid = 1532244 }} * {{cite journal | vauthors = Wu H, Parsons JT | title = Cortactin, an 80/85-kilodalton pp60src substrate, is a filamentous actin-binding protein enriched in the cell cortex. | journal = J. Cell Biol. | volume = 120 | issue = 6 | pages = 1417–26 | year = 1993 | pmid = 7680654 | pmc = 2119758 | doi = 10.1083/jcb.120.6.1417 }} * {{cite journal | vauthors = Brookes S, Lammie GA, Schuuring E, de Boer C, Michalides R, Dickson C, Peters G | title = Amplified region of chromosome band 11q13 in breast and squamous cell carcinomas encompasses three CpG islands telomeric of FGF3, including the expressed gene EMS1. | journal = Genes Chromosomes Cancer | volume = 6 | issue = 4 | pages = 222–31 | year = 1993 | pmid = 7685625 | doi = 10.1002/gcc.2870060406 | s2cid = 36282099 }} * {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. | journal = Gene | volume = 138 | issue = 1–2 | pages = 171–4 | year = 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }} * {{cite journal | vauthors = Schuuring E, Verhoeven E, Litvinov S, Michalides RJ | title = The product of the EMS1 gene, amplified and overexpressed in human carcinomas, is homologous to a v-src substrate and is located in cell-substratum contact sites. | journal = Mol. Cell. Biol. | volume = 13 | issue = 5 | pages = 2891–98 | year = 1993 | pmid = 8474448 | pmc = 359682 | doi = 10.1128/MCB.13.5.2891}} * {{cite journal | vauthors = Maruyama S, Kurosaki T, Sada K, Yamanashi Y, Yamamoto T, Yamamura H | title = Physical and functional association of cortactin with Syk in human leukemic cell line K562. | journal = J. Biol. Chem. | volume = 271 | issue = 12 | pages = 6631–5 | year = 1996 | pmid = 8636079 | doi = 10.1074/jbc.271.26.15615 | doi-access = free }} * {{cite journal | vauthors = van Damme H, Brok H, Schuuring-Scholtes E, Schuuring E | title = The redistribution of cortactin into cell-matrix contact sites in human carcinoma cells with 11q13 amplification is associated with both overexpression and post-translational modification. | journal = J. Biol. Chem. | volume = 272 | issue = 11 | pages = 7374–80 | year = 1997 | pmid = 9054437 | doi = 10.1074/jbc.272.11.7374 | doi-access = free }} * {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library. | journal = Gene | volume = 200 | issue = 1–2 | pages = 149–56 | year = 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }} * {{cite journal | vauthors = Kinnunen T, Kaksonen M, Saarinen J, Kalkkinen N, Peng HB, Rauvala H | title = Cortactin-Src kinase signaling pathway is involved in N-syndecan-dependent neurite outgrowth. | journal = J. Biol. Chem. | volume = 273 | issue = 17 | pages = 10702–8 | year = 1998 | pmid = 9553134 | doi = 10.1074/jbc.273.17.10702 | doi-access = free }} * {{cite journal | vauthors = Kim L, Wong TW | title = Growth factor-dependent phosphorylation of the actin-binding protein cortactin is mediated by the cytoplasmic tyrosine kinase FER. | journal = J. Biol. Chem. | volume = 273 | issue = 36 | pages = 23542–8 | year = 1998 | pmid = 9722593 | doi = 10.1074/jbc.273.36.23542 | doi-access = free }} * {{cite journal | vauthors = Du Y, Weed SA, Xiong WC, Marshall TD, Parsons JT | title = Identification of a novel cortactin SH3 domain-binding protein and its localization to growth cones of cultured neurons. | journal = Mol. Cell. Biol. | volume = 18 | issue = 10 | pages = 5838–51 | year = 1998 | pmid = 9742101 | pmc = 109170 | doi = 10.1128/MCB.18.10.5838}} * {{cite journal | vauthors = Huang C, Liu J, Haudenschild CC, Zhan X | title = The role of tyrosine phosphorylation of cortactin in the locomotion of endothelial cells. | journal = J. Biol. Chem. | volume = 273 | issue = 40 | pages = 25770–6 | year = 1998 | pmid = 9748248 | doi = 10.1074/jbc.273.40.25770 | doi-access = free }} * {{cite journal | vauthors = Katsube T, Takahisa M, Ueda R, Hashimoto N, Kobayashi M, Togashi S | title = Cortactin associates with the cell-cell junction protein ZO-1 in both Drosophila and mouse. | journal = J. Biol. Chem. | volume = 273 | issue = 45 | pages = 29672–7 | year = 1998 | pmid = 9792678 | doi = 10.1074/jbc.273.45.29672 | doi-access = free }} * {{cite journal | vauthors = Ohoka Y, Takai Y | title = Isolation and characterization of cortactin isoforms and a novel cortactin-binding protein, CBP90. | journal = Genes Cells | volume = 3 | issue = 9 | pages = 603–12 | year = 1998 | pmid = 9813110 | doi = 10.1046/j.1365-2443.1998.00216.x | s2cid = 22413036 | doi-access = free }} * {{cite journal | vauthors = Schuuring E, van Damme H, Schuuring-Scholtes E, Verhoeven E, Michalides R, Geelen E, de Boer C, Brok H, van Buuren V, Kluin P | title = Characterization of the EMS1 gene and its product, human Cortactin. | journal = Cell Adhes. Commun. | volume = 6 | issue = 2–3 | pages = 185–209 | year = 1999 | pmid = 9823470 | doi = 10.3109/15419069809004475 | doi-access = free }} * {{cite journal | vauthors = Campbell DH, Sutherland RL, Daly RJ | title = Signaling pathways and structural domains required for phosphorylation of EMS1/cortactin. | journal = Cancer Res. | volume = 59 | issue = 20 | pages = 5376–85 | year = 1999 | pmid = 10537323 }} * {{cite journal | vauthors = Kapus A, Di Ciano C, Sun J, Zhan X, Kim L, Wong TW, Rotstein OD | title = Cell volume-dependent phosphorylation of proteins of the cortical cytoskeleton and cell-cell contact sites. The role of Fyn and FER kinases. | journal = J. Biol. Chem. | volume = 275 | issue = 41 | pages = 32289–98 | year = 2000 | pmid = 10921917 | doi = 10.1074/jbc.M003172200 | doi-access = free }} * {{cite journal | vauthors = Weed SA, Karginov AV, Schafer DA, Weaver AM, Kinley AW, Cooper JA, Parsons JT | title = Cortactin localization to sites of actin assembly in lamellipodia requires interactions with F-actin and the Arp2/3 complex. | journal = J. Cell Biol. | volume = 151 | issue = 1 | pages = 29–40 | year = 2000 | pmid = 11018051 | pmc = 2189811 | doi = 10.1083/jcb.151.1.29 }} {{refend}}
== External links == * {{MeshName|Cortactin}}
{{PDB Gallery|geneid=2017}} {{Adaptor proteins}}
Category:Cell biology Category:Genes on human chromosome 11