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{{Short description|Protein found in humans}}
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'''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 | author = Cosen-Binker LI, Kapus A | title = Cortactin: the gray eminence of the cytoskeleton | journal = Physiology (Bethesda) | volume = 21 | issue = | pages = 352–61 | year = 2006 | month = October | pmid = 16990456 | doi = 10.1152/physiol.00012.2006 | url = | issn = }}</ref><ref name="pmid18615630">{{cite journal | author = 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 | year = 2008 | month = September | pmid = 18615630 | doi = 10.1002/cm.20296 | url = | issn = | pmc = 2561250 }}</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]].
{{Infobox_gene}}
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'''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 ==
== Gene ==
In humans, cortactin is encoded by the ''CTTN'' [[gene]] on chromosome 11.<ref name="pmid7685625">{{cite journal | author = 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 | month = April | pmid = 7685625 | doi = 10.1002/gcc.2870060406| url = | issn = }}</ref>
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 ==
== 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 which are 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 |author = Daly RJ | title = Cortactin signalling and dynamic actin networks | journal = Biochem. J. | volume = 382 | issue = Pt 1 | pages = 13–25 | year = 2004| month = August | pmid = 15186216 | pmc = 1133910 | doi = 10.1042/BJ20040737 | url = }}</ref>
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 ==
== Activation and binding ==
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Cortactin is activated via [[phosphorylation]], by [[tyrosine kinases]] or [[serine/threonine kinases]], in response to extracellular signals like [[growth factors]], [[focal adhesion|adhesion sites]], or [[pathogenic]] invasion of the [[epithelial layer]].
Cortactin is activated via [[phosphorylation]], by [[tyrosine kinases]] or [[serine/threonine kinases]], in response to extracellular signals like [[growth factors]], [[focal adhesion|adhesion sites]], or [[pathogenic]] invasion of the [[epithelial layer]].


The [[SH2 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 [[Microfilament|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 | author = 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 | month = October | pmid = 11018051 | pmc = 2189811 | doi = 10.1083/jcb.151.1.29| url = }}</ref>
The [[SH3 domain]] of certain tyrosine kinases, such as the oncogene [[Src (gene)|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 [[Microfilament|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 [[Extracellular signal-regulated kinases|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 | author = 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 | year = 2004 | month = June | pmid = 15169891 | pmc = 419870 | doi = 10.1128/MCB.24.12.5269-5280.2004 | url = }}</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"/>
Certain serine/threonine kinases, such as [[Extracellular signal-regulated kinases|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 ==
== Location and function in the cell ==


Inactive cortactin is diffuse 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 | author = 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 | year = 2001 | month = March | pmid = 11267876 | doi = 10.1016/S0960-9822(01)00098-7| url = }}</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">{{cite journal | author = 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 | year = 2001 | month = March | pmid = 11267876 | doi = 10.1016/S0960-9822(01)00098-7| url = }}</ref> Thus, polymerization and branching of actin is promoted in areas of the cell where cortactin is localized.
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 | author = Weed SA, Parsons JT | title = Cortactin: coupling membrane dynamics to cortical actin assembly | journal = Oncogene | volume = 20 | issue = 44 | pages = 6418–34 | year = 2001 | month = October | pmid = 11607842 | doi = 10.1038/sj.onc.1204783 | url = }}</ref>
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 mobile 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"/>
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 | author = 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 | year = 2004 | month = July | pmid = 15266049 | pmc = 519036 | doi = 10.1104/pp.104.040683 | url = }}</ref> and clathrin-independent endocytosis.<ref name="Sauvonnet_2005">{{cite journal | author = 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 | year = 2005 | month = January | pmid = 15623579 | pmc = 2171671 | doi = 10.1083/jcb.200406174 | url = }}</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 | author = 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 | year = 2005 | month = February | pmid = 15671060 | doi = 10.1242/jcs.01668 | url = }}</ref>
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 ==
== 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 (medical)|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 | author = 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 | url = }}</ref>
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 (medical)|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==
== Interactions ==
Cortactin has been shown to [[Protein-protein_interaction|interact]] with [[WIPF1]],<ref name=pmid12620186>{{cite journal |doi=10.1016/S0960-9822(03)00107-6 |last=Kinley |first=Andrew W |authorlink= |coauthors=Weed Scott A, Weaver Alissa M, Karginov Andrei V, Bissonette Eric, Cooper John A, Parsons J Thomas |year=[[2003]]|month=Mar. |title=Cortactin interacts with WIP in regulating Arp2/3 activation and membrane protrusion |journal=Curr. Biol. |volume=13 |issue=5 |pages=384–93 |publisher= |location = England| issn = 0960-9822| pmid = 12620186 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref> [[KCNA2]],<ref name=pmid12151401>{{cite journal |last=Hattan |first=David |authorlink= |coauthors=Nesti Edmund, Cachero Teresa G, Morielli Anthony D |year=[[2002]]|month=Oct. |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 |publisher= |location = United States| issn = 0021-9258| pmid = 12151401 |doi = 10.1074/jbc.M205005200 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref> [[FER (gene)|FER]],<ref name=pmid9722593>{{cite journal |doi=10.1074/jbc.273.36.23542 |last=Kim |first=L |authorlink= |coauthors=Wong T W |year=[[1998]]|month=Sep. |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 |publisher= |location = UNITED STATES| issn = 0021-9258| pmid = 9722593 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref> [[CTNND1]],<ref name=pmid12835311>{{cite journal |last=Martinez |first=Maria Cruz |authorlink= |coauthors=Ochiishi Tomoyo, Majewski Michael, Kosik Kenneth S |year=[[2003]]|month=Jul. |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 |publisher= |location = United States| issn = 0021-9525| pmid = 12835311 |doi = 10.1083/jcb.200211025 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = |pmc=2172717 }}</ref> [[SHANK2]],<ref name=pmid9742101>{{cite journal |last=Du |first=Y |authorlink= |coauthors=Weed S A, Xiong W C, Marshall T D, Parsons J T |year=[[1998]]|month=Oct. |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 |publisher= |location = UNITED STATES| issn = 0270-7306| pmid = 9742101 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = |pmc=109170 }}</ref> [[ARPC2]],<ref name=pmid11018051>{{cite journal |doi=10.1083/jcb.151.1.29 |last=Weed |first=S A |authorlink= |coauthors=Karginov A V, Schafer D A, Weaver A M, Kinley A W, Cooper J A, Parsons J T |year=[[2000]]|month=Oct. |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 |publisher= |location = UNITED STATES| issn = 0021-9525| pmid = 11018051 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = |pmc=2189811 }}</ref> [[ACTR3]]<ref name=pmid11018051/><ref name=pmid12176742>{{cite journal |last=Di Ciano |first=Caterina |authorlink= |coauthors=Nie Zilin, Szászi Katalin, Lewis Alison, Uruno Takehito, Zhan Xi, Rotstein Ori D, Mak Alan, Kapus András |year=[[2002]]|month=Sep. |title=Osmotic stress-induced remodeling of the cortical cytoskeleton |journal=Am. J. Physiol., Cell Physiol. |volume=283 |issue=3 |pages=C850–65 |publisher= |location = United States| issn = 0363-6143| pmid = 12176742 |doi = 10.1152/ajpcell.00018.2002 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref> and [[WASL (gene)|WASL]].<ref name=pmid11830518>{{cite journal |last=Mizutani |first=Kiyohito |authorlink= |coauthors=Miki Hiroaki, He Hong, Maruta Hiroshi, Takenawa Tadaomi |year=[[2002]]|month=Feb. |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 |publisher= |location = United States| issn = 0008-5472| pmid = 11830518 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref>


Cortactin has been shown to [[Protein-protein interaction|interact]] with:
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==See also==
* [[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>
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* [[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 (gene)|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 (gene)|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]]
* [[actin]]
* [[gelsolin]]
* [[gelsolin]]
Line 40: Line 51:
* [[villin]]
* [[villin]]


==References==
== References ==
⚫
{{Reflist|35em}}


⚫
== Further reading ==
⚫
{{Reflist|2}}
⚫
{{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 }}
⚫
==Further reading==
* {{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 }}
⚫
{{refbegin | 2}}
* {{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 }}
{{PBB_Further_reading
* {{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 }}
| citations =
*{{cite journal | author=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 }}
* {{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 | author=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 = 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 | author=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 |doi= }}
* {{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 | author=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 |doi=10.1083/jcb.120.6.1417 | pmc=2119758 }}
* {{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 | author=Brookes S, Lammie GA, Schuuring E, ''et al.'' |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 }}
* {{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 | author=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 = 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 | author=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 |doi= | pmc=359682 }}
* {{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 | author=Maruyama S, Kurosaki T, Sada K, ''et al.'' |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 }}
* {{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 | author=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 }}
* {{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 | author=Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, ''et al.'' |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 = 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 | author=Kinnunen T, Kaksonen M, Saarinen J, ''et al.'' |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 }}
* {{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 | author=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 }}
* {{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 | author=Du Y, Weed SA, Xiong WC, ''et al.'' |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 |doi= | pmc=109170 }}
* {{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 | author=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 }}
* {{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 | author=Katsube T, Takahisa M, Ueda R, ''et al.'' |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 }}
* {{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 | author=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 }}
* {{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 }}
*{{cite journal | author=Schuuring E, van Damme H, Schuuring-Scholtes E, ''et al.'' |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 }}
*{{cite journal | author=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 |doi= }}
*{{cite journal | author=Kapus A, Di Ciano C, Sun J, ''et al.'' |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 }}
⚫
*{{cite journal | author=Weed SA, Karginov AV, Schafer DA, ''et al.'' |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 |doi=10.1083/jcb.151.1.29 | pmc=2189811 }}
}}
{{refend}}
{{refend}}
{{PDB Gallery|geneid=2017}}


==External links==
== External links ==
* {{MeshName|Cortactin}}
* {{MeshName|Cortactin}}


⚫
{{PDB Gallery|geneid=2017}}
{{Adaptor proteins}}
{{Adaptor proteins}}

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[[Category:Cell biology]]
[[Category:Cell biology]]
[[Category:Proteins]]
[[Category:Genes on human chromosome 11]]

Latest revision as of 11:30, 27 March 2024

CTTN
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCTTN, EMS1, cortactin
External IDsOMIM: 164765; MGI: 99695; HomoloGene: 3834; GeneCards: CTTN; OMA:CTTN - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2017

13043

Ensembl

ENSG00000085733
ENSG00000288401

ENSMUSG00000031078

UniProt

Q14247

Q60598

RefSeq (mRNA)

NM_001184740
NM_005231
NM_138565

NM_001252572
NM_007803
NM_001357116

RefSeq (protein)

NP_001171669
NP_005222
NP_612632

NP_001239501
NP_031829
NP_001344045

Location (UCSC)Chr 11: 70.4 – 70.44 MbChr 7: 143.99 – 144.02 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Cortactin (from "cortical actin 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.[5][6] 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[edit]

In humans, cortactin is encoded by the CTTN gene on chromosome 11.[7]

Structure[edit]

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.[8]

Activation and binding[edit]

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.[8] 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).[9]

Certain serine/threonine kinases, such as ERK, can phosphorylate cortactin on Ser405 and Ser418 in the SH3 domain.[8] 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.[10] 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.[10] Having other NPFs bind to the Arp2/3 complex at the same time as cortactin may enhance nucleation site stability.[8]

Location and function in the cell[edit]

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.[11] 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.[11] 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.[12]

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.[12]

Studies have implicated cortactin in both clathrin-mediated endocytosis[13] and clathrin-independent endocytosis.[14] 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.[15]

Clinical significance[edit]

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.[16]

Interactions[edit]

Cortactin has been shown to interact with:

See also[edit]

References[edit]

  1. ^ a b c ENSG00000288401 GRCh38: Ensembl release 89: ENSG00000085733, ENSG00000288401 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031078 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Cosen-Binker LI, Kapus A (October 2006). "Cortactin: the gray eminence of the cytoskeleton". Physiology. 21 (5): 352–61. doi:10.1152/physiol.00012.2006. PMID 16990456.
  6. ^ Ammer AG, Weed SA (September 2008). "Cortactin branches out: roles in regulating protrusive actin dynamics". Cell Motil. Cytoskeleton. 65 (9): 687–707. doi:10.1002/cm.20296. PMC 2561250. PMID 18615630.
  7. ^ Brookes S, Lammie GA, Schuuring E, de Boer C, Michalides R, Dickson C, Peters G (April 1993). "Amplified region of chromosome band 11q13 in breast and squamous cell carcinomas encompasses three CpG islands telomeric of FGF3, including the expressed gene EMS1". Genes Chromosomes Cancer. 6 (4): 222–31. doi:10.1002/gcc.2870060406. PMID 7685625. S2CID 36282099.
  8. ^ a b c d Daly RJ (August 2004). "Cortactin signalling and dynamic actin networks". Biochem. J. 382 (Pt 1): 13–25. doi:10.1042/BJ20040737. PMC 1133910. PMID 15186216.
  9. ^ Weed SA, Karginov AV, Schafer DA, Weaver AM, Kinley AW, Cooper JA, Parsons JT (October 2000). "Cortactin localization to sites of actin assembly in lamellipodia requires interactions with F-actin and the Arp2/3 complex". J. Cell Biol. 151 (1): 29–40. doi:10.1083/jcb.151.1.29. PMC 2189811. PMID 11018051.
  10. ^ a b Martinez-Quiles N, Ho HY, Kirschner MW, Ramesh N, Geha RS (June 2004). "Erk/Src phosphorylation of cortactin acts as a switch on-switch off mechanism that controls its ability to activate N-WASP". Mol. Cell. Biol. 24 (12): 5269–80. doi:10.1128/MCB.24.12.5269-5280.2004. PMC 419870. PMID 15169891.
  11. ^ a b Weaver AM, Karginov AV, Kinley AW, Weed SA, Li Y, Parsons JT, Cooper JA (March 2001). "Cortactin promotes and stabilizes Arp2/3-induced actin filament network formation". Curr. Biol. 11 (5): 370–4. Bibcode:2001CBio...11..370W. doi:10.1016/S0960-9822(01)00098-7. PMID 11267876. S2CID 18931911.
  12. ^ a b Weed SA, Parsons JT (October 2001). "Cortactin: coupling membrane dynamics to cortical actin assembly". Oncogene. 20 (44): 6418–34. doi:10.1038/sj.onc.1204783. PMID 11607842.
  13. ^ Samaj J, Baluska F, Voigt B, Schlicht M, Volkmann D, Menzel D (July 2004). "Endocytosis, actin cytoskeleton, and signaling". Plant Physiol. 135 (3): 1150–61. doi:10.1104/pp.104.040683. PMC 519036. PMID 15266049.
  14. ^ Sauvonnet N, Dujeancourt A, Dautry-Varsat A (January 2005). "Cortactin and dynamin are required for the clathrin-independent endocytosis of gammac cytokine receptor". J. Cell Biol. 168 (1): 155–63. doi:10.1083/jcb.200406174. PMC 2171671. PMID 15623579.
  15. ^ Zhu J, Zhou K, Hao JJ, Liu J, Smith N, Zhan X (February 2005). "Regulation of cortactin/dynamin interaction by actin polymerization during the fission of clathrin-coated pits". J. Cell Sci. 118 (Pt 4): 807–17. doi:10.1242/jcs.01668. PMID 15671060. S2CID 25923754.
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Further reading[edit]

External links[edit]

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