Cortactin

Figures & data

Figure 1 Regulation of cellular motility by branched actin and cortactin. Cell motility requires coordination of several processes, including protrusion of the leading edge lamellipodium, adhesion, contraction of actin bundles, and retraction of the rear of the cell. Depicted in the zoomed panels are mechanisms by which cortactin may regulate motility, including: promoting lamellipodial persistence, focal adhesion assembly, cellular signaling and secretion of autocrine factors

Figure 2 Cortactin domain structures. Schematic diagram of key cortactin domains and binding partners. The following abbreviations are used: NT A, N-terminal acidic domain and SH3, Src homology 3 domain. Proteins whose interaction with cortactin has been narrowed down to a particular domain are represented in the same color as the domain on cortactin. Interacting proteins shown in yellow bind the amino terminus of cortactin, which constitute the NT A + repeats domains. Amino acids that are essential for the interaction with key cortactin binding proteins, including W22 for interaction with Arp2/3 and W525 for interactions within the SH3 domain, are shown. The kinases known to phosphorylate cortactin are found above the respective sites they have been shown (or hypothesized) to phosphorylate.

Figure 3 Model of cortactin function at invadopodia. Cortactin is thought to contribute to two major processes in invadopodia: (1) actin polymerization for initiation and/or maturation of invadopodia via activation of N-WASp via Nck, activation of cdc42 via Fgd1, and coactivation of Arp2/3 complex and (2) vesicular trafficking of matrix metalloproteinases to invadopodia via either regulation of post-Golgi trafficking or vesicle capture at invadopodia. Once ECM-degradation is established at invadopodia, they may become longer-lived due to positive feedback.

Table 1 Table of cortactin binding partners

Cortactin binding proteins	Localization	Function	Binding site	References
Arp2/3	Located at branch points of actin filaments network	Actin nucleation	NTA	4, 11
Actin filaments	Cell cytoskeleton	Cytoskeletal polymer	Repeat regions	15
HDAC6	Cytoplasm	Deacetylase	Repeat region	36, 151
SIRT1	Cytoplasmic and nuclear	Deacetylase	Repeat region	37
Caldesmon	Filamentous distribution, lamella and lamellipodia	Actin binding protein, contraction	N-terminus	152
p120 catenin	Cell-cell junction, nucleus, membrane ruffles, actin halos associated with endocytic vesicles	Cell-cell adhesion via cadherin stability & trafficking	N-terminus	81, 153–155
Grb2	Cytoplasm, plasma membrane, lipid rafts, perinuclear region	Signaling adaptor	N-terminus	52, 156, 157
Met	Plasma membrane, dorsal ruffles, early endosomes and late endosomes	Receptor tyrosine kinase	?	52, 158
K^+ channel Kv1.2	Cortical cytoskeleton	Ion channel	?	159
PTP1B	Cytoplasmic face of endoplasmic reticulum	Tyrosine phosphatase	Tyr^446	160, 161
Nck1	Cytoplasmic, cell periphery, podosomes, invadopodia	Signaling adaptor	phospho-Y421, 466	162–164
Syk	Nucleus, cytoplasm, perinuclear region, plasma membrane at cell-cell contacts	Tyrosine kinase	?	53, 58, 165
Src family kinases (Src, Fer)	Cytoplasmic, plasma membrane, focal adhesions, podosomes, invadopodia	Tyrosine kinase	phospho-Y421, 466, 482	55, 56, 70, 71, 166, 167
ERK1/2	Nucleus, cytoplasm	Serine/Threonine kinase	S405, 418	57, 168–170
PAK1	Cytoplasm, plasma membrane, focal adhesions	Serine/Threonine kinase	S113	59, 170–173
CBP90	Cytosol, membrane and synaptic vesicles	?	SH3	33
ZO-1	Cell-cell junction	Tight junction adaptor	SH3	32
BPGAP1	Cytoplasm, plasma membrane	RhoA-GAP	SH3	174, 175
Hip1R	Present at all clathrin patches	Membrane trafficking	SH3	176
BK channels	Plasma membrane	Membrane excitability	SH3	177
ASAP1/AMAP1	Recycling endosomes, focal adhesions, invadopodia, podosomes	ARF6 GAP	SH3	129, 178–181
Abl/Arg	Cytoplasm, nuclear, plasma membrane	Tyrosine kinase	SH3	45, 60, 182, 183
N-WASp	Golgi, Podosomes and invadopodia.	Actin assembly	SH3	97, 184, 185
Dynamin2	Plasma membrane, trans-Golgi network, cell cortex, cortical ruffles	GTP ase, Membrane trafficking	SH3	186–189
CortBP1/SHANK2	Within secretory granules (cytoplasm), membrane ruffles, neuronal growth cones, lipid rafts	Synaptic plasticity, adaptor protein, regulates Na^+/H^+ exchanger 3	SH3	190–195
FGD1	Cytoplasm, Golgi, cell cortex and membrane ruffles	Cdc42-GEF	SH3	196, 197
WIP	Perinuclear region, membrane ruffles	Adaptor protein, Actin binding/assembly, WASp stabilization	SH3	68, 198–200
Non-muscle myosin light chain kinase	Actin stress fibers, lamellipodia	Contraction	SH3	47, 201, 202
Missing in metastasis (MIM)	Plasma membrane, actin bundles, stress fibers, cytoplasm	Adaptor protein, Actin binding and regulation	SH3	203, 204
CD2AP	Cell membrane, endosomes, immune synapse (T cells)	Endocytosis (binds to Rab4 & c-Cbl)	SH3	205–210

List of Cortactin binding proteins

Svitkina TM, Borisy GG. Arp2/3 complex and actin depolymerizing factor/cofilin in dendritic organization and treadmilling of actin filament array in lamellipodia. J Cell Biol 1999; 145:1009 - 1026

 PubMed Web of Science ®Google Scholar

Weed SA, Karginov AV, Schafer DA, Weaver AM, Kinley AW, Cooper JA, et al. Cortactin localization to sites of actin assembly in lamellipodia requires interactions with F-actin and the Arp2/3 complex. J Cell Biol 2000; 151:29 - 40

 PubMedGoogle Scholar

Wu H, Parsons JT. Cortactin, an 80/85 kilodalton pp60src substrate, is a filamentous actin-binding protein enriched in the cell cortex. J Cell Biol 1993; 120:1417 - 1426

 PubMed Web of Science ®Google Scholar

Zhang X, Yuan Z, Zhang Y, Yong S, Salas-Burgos A, Koomen J, et al. HDAC6 modulates cell motility by altering the acetylation level of cortactin. Mol Cell 2007; 27:197 - 213

 PubMed Web of Science ®Google Scholar

Bertos NR, Gilquin B, Chan GK, Yen TJ, Khochbin S, Yang XJ. Role of the tetradecapeptide repeat domain of human histone deacetylase 6 in cytoplasmic retention. J Biol Chem 2004; 279:48246 - 48254

 PubMed Web of Science ®Google Scholar

Zhang Y, Zhang M, Dong H, Yong S, Li X, Olashaw N, et al. Deacetylation of cortactin by SIRT1 promotes cell migration. Oncogene 2009; 28:445 - 460

 PubMed Web of Science ®Google Scholar

Huang R, Cao GJ, Guo H, Kordowska J, Albert Wang CL. Direct interaction between caldesmon and cortactin. Arch Biochem Biophys 2006; 456:175 - 182

 PubMed Web of Science ®Google Scholar

Boguslavsky S, Grosheva I, Landau E, Shtutman M, Cohen M, Arnold K, et al. p120 catenin regulates lamellipodial dynamics and cell adhesion in cooperation with cortactin. Proc Natl Acad Sci USA 2007; 104:10882 - 10887

 Google Scholar

Chen X, Kojima S, Borisy GG, Green KJ. p120 catenin associates with kinesin and facilitates the transport of cadherin-catenin complexes to intercellular junctions. J Cell Biol 2003; 163:547 - 557

 PubMedGoogle Scholar

Davis MA, Ireton RC, Reynolds AB. A core function for p120-catenin in cadherin turnover. J Cell Biol 2003; 163:525 - 534

 PubMed Web of Science ®Google Scholar

Crostella L, Lidder S, Williams R, Skouteris GG. Hepatocyte Growth Factor/scatter factor-induces phosphorylation of cortactin in A431 cells in a Src kinase-independent manner. Oncogene 2001; 20:3735 - 3745

 PubMed Web of Science ®Google Scholar

Stork B, Engelke M, Frey J, Horejsi V, Hamm-Baarke A, Schraven B, et al. Grb2 and the non-T cell activation linker NTAL constitute a Ca(2+)-regulating signal circuit in B lymphocytes. Immunity 2004; 21:681 - 691

 PubMed Web of Science ®Google Scholar

Di Fulvio M, Frondorf K, Henkels KM, Lehman N, Gomez-Cambronero J. The Grb2/PLD2 interaction is essential for lipase activity, intracellular localization and signaling in response to EGF. J Mol Biol 2007; 367:814 - 824

 PubMedGoogle Scholar

Abella JV, Parachoniak CA, Sangwan V, Park M. Dorsal ruffle microdomains potentiate Met receptor tyrosine kinase signaling and downregulation. J Biol Chem 285:24956 - 24967

 PubMed Web of Science ®Google Scholar

Hattan D, Nesti E, Cachero TG, Morielli AD. Tyrosine phosphorylation of Kv1.2 modulates its interaction with the actin-binding protein cortactin. J Biol Chem 2002; 277:38596 - 38606

 PubMed Web of Science ®Google Scholar

Frangioni JV, Beahm PH, Shifrin V, Jost CA, Neel BG. The nontransmembrane tyrosine phosphatase PTP-1B localizes to the endoplasmic reticulum via its 35 amino acid C-terminal sequence. Cell 1992; 68:545 - 560

 PubMed Web of Science ®Google Scholar

Stuible M, Dube N, Tremblay ML. PTP1B regulates cortactin tyrosine phosphorylation by targeting Tyr446. J Biol Chem 2008; 283:15740 - 15746

 PubMed Web of Science ®Google Scholar

Okamura H, Resh MD. p80/85 cortactin associates with the Src SH2 domain and colocalizes with v-Src in transformed cells. J Biol Chem 1995; 270:26613 - 26618

 PubMed Web of Science ®Google Scholar

Oser M, Mader CC, Gil-Henn H, Magalhaes M, Bravo-Cordero JJ, Koleske AJ, et al. Specific tyrosine phosphorylation sites on cortactin regulate Nck1-dependent actin polymerization in invadopodia. J Cell Sci 123:3662 - 3673

 PubMed Web of Science ®Google Scholar

Gallet C, Rosa JP, Habib A, Lebret M, Levy-Toledano S, Maclouf J. Tyrosine phosphorylation of cortactin associated with Syk accompanies thromboxane analogue-induced platelet shape change. J Biol Chem 1999; 274:23610 - 23616

 PubMed Web of Science ®Google Scholar

Maruyama S, Kurosaki T, Sada K, Yamanashi Y, Yamamoto T, Yamamura H. Physical and functional association of cortactin with Syk in human leukemic cell line K562. J Biol Chem 1996; 271:6631 - 6635

 PubMed Web of Science ®Google Scholar

Zhang X, Shrikhande U, Alicie BM, Zhou Q, Geahlen RL. Role of the protein tyrosine kinase Syk in regulating cell-cell adhesion and motility in breast cancer cells. Mol Cancer Res 2009; 7:634 - 644

 PubMed Web of Science ®Google Scholar

Kapus A, Di Ciano C, Sun J, Zhan X, Kim L, Wong TW, et al. Cell volume-dependent phosphorylation of proteins of the cortical cytoskeleton and cell-cell contact sites. The role of Fyn and FER kinases. J Biol Chem 2000; 275:32289 - 32298

 PubMed Web of Science ®Google Scholar

Kim L, Wong TW. Growth factor-dependent phosphorylation of the actin-binding protein cortactin is mediated by the cytoplasmic tyrosine kinase FER. J Biol Chem 1998; 273:23542 - 23548

 PubMed Web of Science ®Google Scholar

Head JA, Jiang D, Li M, Zorn LJ, Schaefer EM, Parsons JT, et al. Cortactin tyrosine phosphorylation requires Rac1 activity and association with the cortical actin cytoskeleton. Mol Biol Cell 2003; 14:3216 - 3229

 PubMed Web of Science ®Google Scholar

Huang C, Liu J, Haudenschild CC, Zhan X. The role of tyrosine phosphorylation of cortactin in the locomotion of endothelial cells. J Biol Chem 1998; 273:25770 - 25776

 PubMed Web of Science ®Google Scholar

Linder S, Aepfelbacher M. Podosomes: adhesion hotspots of invasive cells. Trends Cell Biol 2003; 13:376 - 385

 PubMed Web of Science ®Google Scholar

Spinardi L, Rietdorf J, Nitsch L, Bono M, Tacchetti C, Way M, et al. A dynamic podosome-like structure of epithelial cells. Exp Cell Res 2004; 295:360 - 374

 PubMed Web of Science ®Google Scholar

Martinez-Quiles N, Ho HY, Kirschner MW, Ramesh N, Geha RS. Erk/Src phosphorylation of cortactin acts as a switch on-switch off mechanism that controls its ability to activate N-WASP. Mol Cell Biol 2004; 24:5269 - 5280

 PubMed Web of Science ®Google Scholar

Campbell DH, Sutherland RL, Daly RJ. Signaling pathways and structural domains required for phosphorylation of EMS1/cortactin. Cancer Res 1999; 59:5376 - 5385

 PubMed Web of Science ®Google Scholar

Widmann C, Gibson S, Jarpe MB, Johnson GL. Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol Rev 1999; 79:143 - 180

 PubMed Web of Science ®Google Scholar

Webb BA, Zhou S, Eves R, Shen L, Jia L, Mak AS. Phosphorylation of cortactin by p21-activated kinase. Arch Biochem Biophys 2006; 456:183 - 193

 PubMed Web of Science ®Google Scholar

Lu W, Mayer BJ. Mechanism of activation of Pak1 kinase by membrane localization. Oncogene 1999; 18:797 - 806

 PubMed Web of Science ®Google Scholar

Ohoka Y, Takai Y. Isolation and characterization of cortactin isoforms and a novel cortactin-binding protein, CBP90. Genes Cells 1998; 3:603 - 612

 PubMed Web of Science ®Google Scholar

Katsube T, Takahisa M, Ueda R, Hashimoto N, Kobayashi M, Togashi S. Cortactin associates with the cell-cell junction protein ZO-1 in both Drosophila and mouse. J Biol Chem 1998; 273:29672 - 29677

 Google Scholar

Shang X, Zhou YT, Low BC. Concerted regulation of cell dynamics by BNIP-2 and Cdc42GAP homology/Sec14p-like, proline-rich and GTPase-activating protein domains of a novel Rho GTPase-activating protein, BPGAP1. J Biol Chem 2003; 278:45903 - 45914

 PubMed Web of Science ®Google Scholar

Lua BL, Low BC. BPGAP1 interacts with cortactin and facilitates its translocation to cell periphery for enhanced cell migration. Mol Biol Cell 2004; 15:2873 - 2883

 PubMed Web of Science ®Google Scholar

Le Clainche C, Pauly BS, Zhang CX, Engqvist-Goldstein AE, Cunningham K, Drubin DG. A Hip1R-cortactin complex negatively regulates actin assembly associated with endocytosis. EMBO J 2007; 26:1199 - 1210

 PubMed Web of Science ®Google Scholar

Tian L, Chen L, McClafferty H, Sailer CA, Ruth P, Knaus HG, et al. A noncanonical SH3 domain binding motif links BK channels to the actin cytoskeleton via the SH3 adapter cortactin. FASEB J 2006; 20:2588 - 2590

 PubMed Web of Science ®Google Scholar

Onodera Y, Hashimoto S, Hashimoto A, Morishige M, Mazaki Y, Yamada A, et al. Expression of AMAP1, an ArfGAP, provides novel targets to inhibit breast cancer invasive activities. EMBO J 2005; 24:963 - 973

 PubMed Web of Science ®Google Scholar

Randazzo PA, Andrade J, Miura K, Brown MT, Long YQ, Stauffer S, et al. The Arf GTPase-activating protein ASAP1 regulates the actin cytoskeleton. Proc Natl Acad Sci USA 2000; 97:4011 - 4016

 PubMed Web of Science ®Google Scholar

Morishige M, Hashimoto S, Ogawa E, Toda Y, Kotani H, Hirose M, et al. GEP100 links epidermal growth factor receptor signalling to Arf6 activation to induce breast cancer invasion. Nat Cell Biol 2008; 10:85 - 92

 PubMed Web of Science ®Google Scholar

Boyle SN, Michaud GA, Schweitzer B, Predki PF, Koleske AJ. A critical role for cortactin phosphorylation by Abl-family kinases in PDGF-induced dorsal-wave formation. Curr Biol 2007; 17:445 - 451

 PubMed Web of Science ®Google Scholar

Lapetina S, Mader CC, Machida K, Mayer BJ, Koleske AJ. Arg interacts with cortactin to promote adhesion-dependent cell edge protrusion. J Cell Biol 2009; 185:503 - 519

 PubMedGoogle Scholar

Taagepera S, McDonald D, Loeb JE, Whitaker LL, McElroy AK, Wang JY, et al. Nuclear-cytoplasmic shuttling of C-ABL tyrosine kinase. Proc Natl Acad Sci USA 1998; 95:7457 - 7462

 PubMed Web of Science ®Google Scholar

Zipfel PA, Zhang W, Quiroz M, Pendergast AM. Requirement for Abl kinases in T cell receptor signaling. Curr Biol 2004; 14:1222 - 1231

 PubMed Web of Science ®Google Scholar

Yamaguchi H, Lorenz M, Kempiak S, Sarmiento C, Coniglio S, Symons M, et al. Molecular mechanisms of invadopodium formation: the role of the N-WASPArp2/3 complex pathway and cofilin. J Cell Biol 2005; 168:441 - 452

 PubMed Web of Science ®Google Scholar

Matas OB, Martinez-Menarguez JA, Egea G. Association of Cdc42/N-WASP/Arp2/3 signaling pathway with Golgi membranes. Traffic 2004; 5:838 - 846

 PubMed Web of Science ®Google Scholar

Mizutani K, Miki H, He H, Maruta H, Takenawa T. Essential role of neural Wiskott-Aldrich syndrome protein in podosome formation and degradation of extracellular matrix in src-transformed fibroblasts. Cancer Res 2002; 62:669 - 674

 PubMed Web of Science ®Google Scholar

Henley JR, McNiven MA. Association of a dynamin-like protein with the Golgi apparatus in mammalian cells. J Cell Biol 1996; 133:761 - 775

 PubMed Web of Science ®Google Scholar

McNiven MA, Kim L, Krueger EW, Orth JD, Cao H, Wong TW. Regulated interactions between dynamin and the actin-binding protein cortactin modulate cell shape. J Cell Biol 2000; 151:187 - 198

 PubMed Web of Science ®Google Scholar

Redecker P, Bockmann J, Bockers TM. Secretory granules of hypophyseal and pancreatic endocrine cells contain proteins of the neuronal postsynaptic density. Cell Tissue Res 2007; 328:49 - 55

 PubMed Web of Science ®Google Scholar

McWilliams RR, Gidey E, Fouassier L, Weed SA, Doctor RB. Characterization of an ankyrin repeat-containing Shank2 isoform (Shank2E) in liver epithelial cells. Biochem J 2004; 380:181 - 191

 PubMed Web of Science ®Google Scholar

Hou P, Estrada L, Kinley AW, Parsons JT, Vojtek AB, Gorski JL. Fgd1, the Cdc42 GEF responsible for Faciogenital Dysplasia, directly interacts with cortactin and mAbp1 to modulate cell shape. Hum Mol Genet 2003; 12:1981 - 1993

 PubMedGoogle Scholar

Estrada L, Caron E, Gorski JL. Fgd1, the Cdc42 guanine nucleotide exchange factor responsible for faciogenital dysplasia, is localized to the subcortical actin cytoskeleton and Golgi membrane. Hum Mol Genet 2001; 10:485 - 495

 PubMed Web of Science ®Google Scholar

Kinley AW, Weed SA, Weaver AM, Karginov AV, Bissonette E, Cooper JA, et al. Cortactin interacts with WIP in regulating Arp2/3 activation and membrane protrusion. Curr Biol 2003; 13:384 - 393

 PubMedGoogle Scholar

Le Bras S, Massaad M, Koduru S, Kumar L, Oyoshi MK, Hartwig J, et al. WIP is critical for T cell responsiveness to IL-2. Proc Natl Acad Sci USA 2009; 106:7519 - 7524

 PubMed Web of Science ®Google Scholar

de la Fuente MA, Sasahara Y, Calamito M, Anton IM, Elkhal A, Gallego MD, et al. WIP is a chaperone for Wiskott-Aldrich syndrome protein (WASP). Proc Natl Acad Sci USA 2007; 104:926 - 931

 PubMed Web of Science ®Google Scholar

Dudek SM, Jacobson JR, Chiang ET, Birukov KG, Wang P, Zhan X, et al. Pulmonary endothelial cell barrier enhancement by sphingosine 1-phosphate: roles for cortactin and myosin light chain kinase. J Biol Chem 2004; 279:24692 - 24700

 PubMed Web of Science ®Google Scholar

Brown M, Adyshev D, Bindokas V, Moitra J, Garcia JG, Dudek SM. Quantitative distribution and colocalization of non-muscle myosin light chain kinase isoforms and cortactin in human lung endothelium. Microvasc Res 80:75 - 88

 PubMed Web of Science ®Google Scholar

Dudek SM, Birukov KG, Zhan X, Garcia JG. Novel interaction of cortactin with endothelial cell myosin light chain kinase. Biochem Biophys Res Commun 2002; 298:511 - 519

 PubMed Web of Science ®Google Scholar

Lin J, Liu J, Wang Y, Zhu J, Zhou K, Smith N, et al. Differential regulation of cortactin and N-WASP-mediated actin polymerization by missing in metastasis (MIM) protein. Oncogene 2005; 24:2059 - 2066

 PubMed Web of Science ®Google Scholar

Gonzalez-Quevedo R, Shoffer M, Horng L, Oro AE. Receptor tyrosine phosphatase-dependent cytoskeletal remodeling by the hedgehog-responsive gene MIM/BEG4. J Cell Biol 2005; 168:453 - 463

 PubMed Web of Science ®Google Scholar

Lynch DK, Winata SC, Lyons RJ, Hughes WE, Lehrbach GM, Wasinger V, et al. A Cortactin-CD2-associated protein (CD2AP) complex provides a novel link between epidermal growth factor receptor endocytosis and the actin cytoskeleton. J Biol Chem 2003; 278:21805 - 21813

 PubMed Web of Science ®Google Scholar

Cormont M, Meton I, Mari M, Monzo P, Keslair F, Gaskin C, et al. CD2AP/CMS regulates endosome morphology and traffic to the degradative pathway through its interaction with Rab4 and c-Cbl. Traffic 2003; 4:97 - 112

 PubMed Web of Science ®Google Scholar