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REVIEW

Cortactin: The Gray Eminence of the Cytoskeleton

Laura I. Cosen-Binker and András Kapus

Saint Michael’s Hospital Research Institute and Department of Surgery, University of Toronto, Toronto, Ontario, Canada, kapusa{at}smh.toronto.on.ca

	Abstract

 
Cortactin, an actin filament-binding protein and target of multiple kinases, has emerged as a central element connecting signaling pathways with cytoskeleton restructuring. It is involved in a perplexingly diverse array of cellular processes, including cell motility, invasiveness, synaptogenesis, endocytosis, intercellular contact assembly, and host-pathogen interactions, where the common denominator appears to be a role in the coordination of membrane dynamics with cytoskeletal remodeling. Although in recent years our knowledge about cortactin has increased exponentially, the exact mechanisms underlying its fundamental roles remain to be defined.

	Introduction

Top Introduction Cortactin in the Test... Cortactin at the Lamellipodia... Cortactin at Invadopodia and... Cortactin at the Growth... Cortactin at Endocytic Vesicles Cortactin at Intercellular... Cortactin at Sites of... Cortactin in the Future References

 
Cortactin was discovered 15 years ago in Thomas Parson’s laboratory as a filamentous actin-binding protein and a major substrate of the oncogenic tyrosine kinase v-Src (104, 105). These two signature features (F-actin binding and phosphorylation by various kinases) have initiated the continuously growing career of this protein and focused attention on cortactin as a candidate molecule that might link structural (cytoskeletal) organization with signal transduction. The recognition that cortactin binds to and potentiates the activity of the actin-related protein 2/3 (Arp2/3) complex (94, 98, 102), a recently discovered central actin-nucleating factor (36), gave strong experimental support for this notion. Moreover, in addition to being a likely bridge between receptor-mediated or mechanical signals on one hand and actin skeleton restructuring on the other, cortactin has emerged as a key protein involved in the coordination of membrane dynamics and cytoskeleton remodeling (81). Indeed cortactin is always "there" when changes in the cortical actin skeleton initiate, modify, or accompany major membrane events. Thus cortactin accumulates in lamellipodia where the freshly polymerized F-actin meshwork pushes the membrane envelope of migrating cells (8, 61, 101) at the leading edge of path-finding axons (15, 52, 53); in the invadopodia by which metastatic tumor cells penetrate the basement membrane (5, 6); in podosomes, where bone-resorbing osteoclasts seal off the surface to be digested (21, 60); at intercellular contacts, where cells strengthen or disassemble their bonds (27, 28, 34); around endocytic vesicles, which move toward the cytosol in an actin-dependent manner (12, 45); at the entry sites of intra-cellular pathogens, which propel themselves by harnessing the F-actin polymerization machinery (for review, see Ref. 85); or at the periphery of mechanically challenged cells, which reinforce their cytoskeleton (3, 22). Clearly, the common denominator of these diverse events is not simply the presence of F-actin but the formation of a dynamic membrane-cytoskeleton interface, since other F-actin-rich structures, such as stress fibers, do not contain cortactin.

Despite the substantial size of the cortactin literature (currently the word "cortactin" appears in 339 articles), the most fundamental questions are still open. Thus, although cortactin has been implicated in the above-mentioned processes, its exact role is still not clearly defined. Its obvious participation in many of these fundamental events together with the elusiveness of its exact role render cortactin the gray eminence of the cytoskeleton. Moreover, the role of tyrosine (and serine/threonine) phosphorylation in the regulation of its function, localization, and interaction with other proteins is also far from being fully understood. Thus both the regulation of cortactin and the regulation by cortactin remain a challenge of cytoskeletal biology. Furthermore, cortactin has established itself as a medically important protein, since it is not only overexpressed in a variety of human cancers but appears to play a causative role in tumor cell migration and metastasis (58, 74).

In the past few years, cortactin was the focus of several excellent reviews (19, 62, 85, 103). In this short overview, we would like to approach the topic from a physiological point of view, or, more precisely, we attempt to provide a "topical physiology" of cortactin by summarizing the various loci where cortactin acts and the associated cell biological processes in which it appears to participate. We have to start, however, with a more detailed look at its biochemistry and genetics.

	Cortactin in the Test Tube

Top Introduction Cortactin in the Test... Cortactin at the Lamellipodia... Cortactin at Invadopodia and... Cortactin at the Growth... Cortactin at Endocytic Vesicles Cortactin at Intercellular... Cortactin at Sites of... Cortactin in the Future References

 
The cortactin family is composed of two gene products: the ubiquitously expressed cortactin with its alternatively spliced variants and the hematopoietic lineage cell-specific protein (HS1), present exclusively in blood cells (84, 96). Human cortactin is encoded by the CTTN (formerly EMS1) gene within the chromosome region 11q13, a locus often amplified in various tumors, including carcinomas of the head and neck, ovary, breast, liver, and lung (16, 74, 77, 83). Amplification of the cortactin gene or increased expression of the cortactin mRNA [e.g., in bladder cancer (7)] is associated with metastasis and poor prognosis, implicating cortactin as a factor in invasiveness. The cortactin protein is composed of ~550 amino acids (FIGURE 1A). The N-terminal half of the molecule includes the N-terminal acidic region (NTA), which harbors the DDW motif, the binding site for the Arp3 component of the Arp2/3 complex, followed by 6.5 tandem repeats of 37 amino acids responsible for F-actin binding (103). Thus this half of the molecule is responsible for coupling cortactin to structural elements of the cytoskeleton. The COOH-terminal half is composed of an -helical domain of unknown function, followed by a proline-serine-threonine-rich region (PST), which also harbors critical tyrosine residues, and finally a Src homology 3 (SH3) domain. Thus the COOH-terminal half of cortactin can be regarded as the regulatory segment of the protein: the PST is a target of various serine/threonine kinases, of which p21-activated kinase (PAK) (97) and the MAP kinase ERK (11, 64) have been identified and implicated in the phosphorylation of S405 and S418, whereas three critical tyrosine residues (Y421/466/482) are targeted (directly or indirectly) by members of the Src kinase family v-Src, c-Src, and Fyn (39, 46, 47, 104); other non-receptor tyrosine kinases such as FER (46, 50) and Syk (30); and the hepatocytes growth factor receptor kinase MET (18). The SH3 domain is a hub of interactions through which cortactin has been shown to associate with the proline-rich regions of a plethora of proteins, thereby linking cortactin-mediated actin remodeling to the various specific loci and processes. The SH3-binding partners include the Arp2/3-stimulating Wiscott-Aldrich protein N-WASP (70) and the WASP-interacting protein WIP (51), missing in metastasis protein MIM (59), the endocytic GTPase dynamin-2 (67), the receptor endocytosis-regulator scaffold CD2AP (63), the tight junction (TJ) protein ZO-1, the synaptic adaptor protein Shank2 (23), the Cdc42 activator guanine nucleotide exchange factor (GEF) faciogenital dysplasia 1 (FGD1) (37), CBP90, a brain- and mammary gland-specific protein of unknown function (44, 72), and the contractility-enhancing myosin light chain kinase (24). This list clearly indicates that a remarkably diverse array of processes employs cortactin as their link to cytoskele-ton remodeling.

View larger version (17K): [in this window] [in a new window]   FIGURE 1. The structure and interactions of cortactin A: the various functional domains are shown on top, whereas the different proteins cortactin binds to and the kinases that phosphorylate it are indicated at bottom. B: dendritic nucleation. The activated Arp2/3 complex binds to the side of a mother filament (M) to nucleate a daughter filament (D). The schemes show two potential (nonexclusive) configurations of cortactin arrangement near the branch point. In both cases, the N terminus of cortactin binds to the Arp2/3 complex, whereas the F-actin binding repeats interact either with the daughter filament or with the mother filament as suggested in Refs. 93 and 98, respectively. During the finalization of this review, Pant et al. (76) published a study in which they used electron microscopy and three-dimensional reconstruction to investigate the geometry of the interaction between purified actin and the cortactin N terminus. They found that binding of cortactin to actin subdomain-1 widens the gap between the intertwining actin filaments. They propose a model in which cortactin binding to the mother filament might facilitate the recruitment of WASP at this locus. The COOH terminal SH3 domain can associate with a variety of partners (X).

The question arises how cortactin phosphorylation affects its actin-nucleating activity. This is a simple question with no clear answer. There is no evidence that tyrosine (or serine) phosphorylation would directly affect the Arp2/3-stimulating effect of cortactin. However, phosphorylation can modify the interaction of cortactin with other proteins, which may have a major impact. Recently, an "on-off switch" or "SY switch" paradigm has been put forward, according to which ERK-mediated serine phosphorylation (S) promotes, whereas Src-mediated tyrosine phosphorylation (Y) inhibits, the SH3-dependent interaction of cortactin with WASP and the consequent actin polymerization (64). This view assigns a negative (off) role for tyrosine phosphorylation, which is consistent with previous findings that osmotic stress-induced tyrosine phosphorylation promotes the disassembly of cortactin and Arp3 (22). However, the picture is bound to be more complex since cortactin tyrosine phosphorylation is associated with and appears to be necessary for many positive functions (e.g., invasiveness; see next sections) as well. Moreover, although the concept that phosphorylation modifies the availability of SH3 is an attractive one, this does not have to be always negative for tyrosine and positive for serine phosphorylation. Rather, phosphorylation may selectively alter the relative affinity for individual partners. Consistent with such a notion, tyrosine phosphorylation seems to promote the SH3-dependent binding of cortactin to the adaptor protein CD2AP (63), to myosin light-chain kinase (MLCK) (24), and according to our preliminary data to dynamin. Furthermore, serine phosphorylation in itself may be neither sufficient nor necessary to induce cortactin translocation to the cortical skeleton (42). Conceivably, an initial assembly of the F-actin-Arp2/3 complex might be enough to recruit cortactin. In addition to regulating SH3 affinity, tyrosine phosphorylation may promote SH2 domain-dependent interactions [e.g., with Fer and Src (50, 73)] and was suggested to decrease the actin cross-linking or bundling activity of cortactin (39). However, the actin cross-linking capability of cortactin is disputed, and the molecular basis of such an effect is not clear (103). Finally, tyrosine phosphorylation may also regulate the cellular level of cortactin, since the phosphorylated form is preferentially degraded by the protease calpain (40).

What may be necessary for proper cortactin function is not as much a net change in serine or tyrosine phosphorylation but a continuous cycle of phosphorylation and dephosphorylation allowing the dynamic recycling of the protein. Thus we proposed that tyrosine phosphorylation might be required to mobilize cortactin that had been incorporated into the F-actin meshwork (29). This way cortactin may be liberated from the base of the lamellipodium, and after dephosphorylation it may be re-incorporated at the rapidly protruding leading edge. Consistent with this model, actin organization per se impacts on cortactin phosphorylation: actin depolymerization promotes Fer-mediated cortactin phosphorylation, whereas cortactin associated with F-actin seems to be less accessible for tyrosine phosphorylation (29). Future studies should test the phosphorylation-dependent recycling model.

	Cortactin at the Lamellipodia and the Leading Edge

Top Introduction Cortactin in the Test... Cortactin at the Lamellipodia... Cortactin at Invadopodia and... Cortactin at the Growth... Cortactin at Endocytic Vesicles Cortactin at Intercellular... Cortactin at Sites of... Cortactin in the Future References

 
A variety of growth factors, e.g., PDGF, EGF (48, 101), sphingosine-1-phosphate (56), shear stress (25), and hyperosmotic shock (22), send cortactin, presumably via the activation of the small GTPase Rac (101), to the cell periphery and induce its accumulation in lamellipodia and membrane ruffles (FIGURE 2A). Tyrosine phosphorylation of cortactin is not required for this process (22, 33); rather, it might be a consequence of translocation (33) or independent from it (22, 29). Consistent with a functional role, cortactin overexpression enhances cell migration (38, 78), tyrosine phosphorylation-incompetent or SH3-deleted mutants reduce the motility of fibroblasts and epithelial cells (38, 54), and siRNA-mediated cortactin downregulation inhibits cell migration and matrigel invasion of breast epithelial (95) or mammary carcinoma cells. These observations and the biochemical properties of cortactin would suggest that this protein is indispensable for lamellipodium formation and analogous phenomena such as cell spreading. However, rather surprisingly, the overall picture is not as clear and is not devoid of contradictions. For example, Bryce et al. (8) found that cortactin was necessary for lamellipodial persistence, i.e., in the absence of cortactin, peripheral protrusions were instable and rapidly retracted, consistent with a branch-stabilizing role. In contrast, Kempiak et al. (48) reported that, on cortactin down-regulation, mammary tumor cells exhibited enhanced lamellipod-like extension toward EGF-covered beads, although their overall motility was less. Furthermore, using the same cell type, it was found that cortactin downregulation resulted in near-normal EGF-induced lamellipod extension but delayed lamellipod retraction (S. Weed, personal communication), whereas our studies in the same system showed a grossly impaired lamellipod extension that was restored by cortactin retransfection, an effect requiring both the critical tyrosines and the SH3 domain (17). Moreover, Illes et al. (43) reported that siRNA-mediated reduction in cortactin caused 70% inhibition of cell spreading, whereas van Rossum et al. (95) found that the absence of cortactin accelerated spreading and increased the overall spread area by 25–50%. In this study, lamellipod extension was not affected by cortactin downregulation, letting the authors conclude that cortactin is either not required for this process or the remaining cortactin after siRNA treatment might be sufficient. Thus, whereas everybody agrees that cortactin and its tyrosine phosphorylation are important for efficient cell migration, the role of cortactin in the subtleties of lamellipodial dynamics remains unresolved. In addition to modifying F-actin dynamics at the tip of the leading edge, another way how cortactin might affect lamellipodial dynamics is via an impact on the assembly of focal adhesions at the base of the lamellipodium. Normal focal contacts appear to be required for the generation of a continuous, broad lamellipodium at the leading edge (91), and cortactin downregulation decreased the rate of peripheral adhesion assembly as visualized by GFP-paxillin (8).

View larger version (68K): [in this window] [in a new window]   FIGURE 2. The playgrounds of cortactin Cortactin, as a key organizer and coordinator of cytoskeleton remodeling and membrane dynamics, accumulates in various functional hot spots. It is highly enriched in lamellipodia (A), in which the branching F-actin meshwork pushes the membrane envelope of migrating cells. It is also necessary for the formation and function of invadopodia (B) and podosomes (C), two important matrix-membrane interfaces. The presence of cortactin is required for the efficient recruitment of the matrix-degrading metalloproteases (MMP) to invadopodia (B). In these structures, cortactin forms a complex with paxillin and protein kinase C (PKC). In podosomes (or foot processes), cortactin is a constituent of the central actin column (core), which is connected to the matrix by a peripheral ring structure, composed of integrins, and adaptors proteins (vinculin, paxillin). Cortactin is a dynamic regulator of the excitatory synapse as well (D), where it links the adaptor protein Shank to the cytoskeleton. Shank is coupled to ionotropic (I) glutamate receptors through the postsynaptic density protein-95 (PSD) and the guanylate kinase-associated protein (GKAP), and to metabotropic (M) glutamate receptors through Homer. Cortactin (via its tyrosine phosphorylation) regulates the stability of the postsynaptic density. Cortactin is a key component of the endocytic machinery too (E), where it may participate in the invagination of the forming endosomes and the coordination of this process with vesicle scission through interaction with dynamin. Subsequently, cortactin may contribute to the actin comet tail-driven intracellular movement of the formed vesicle. Cortactin has been implicated as a regulator of various intercellular junctions (F). It associates with tight junctions (TJ) through Zonula occludens 1 (ZO-1). Its role is better understood in adherens junctions (AJ), composed of intercellular adhesion molecules cadherins (cad) connected to the actin skeleton via ß-catenin (ß) and catenin (). Currently, it is not clear whether cortactin associates with cadherins directly or through yet unidentified protein(s) (designated with "?" in the figure). Cortactin is important for cytoskeletal organization at the AJs, a requisite for junction formation and strengthening. Local tyrosine phosphorylation of cortactin by Fer is required for this process.

	Cortactin at Invadopodia and Podosomes

Top Introduction Cortactin in the Test... Cortactin at the Lamellipodia... Cortactin at Invadopodia and... Cortactin at the Growth... Cortactin at Endocytic Vesicles Cortactin at Intercellular... Cortactin at Sites of... Cortactin in the Future References

 
There is consensus with regard to the requirement of cortactin for invasiveness and for the formation and function of invadopodia. These structures are ventral membrane protrusions or finger-like processes that penetrate into the surrounding extracellular matrix (ECM) and contain proteolytic enzymes such as matrix metalloproteases (66) (FIGURE 2B). Cortactin is highly enriched in invadopodia where it forms a complex with paxillin and protein kinase C µ (PKCµ). Importantly, microinjection of anti-cortactin antibodies suppressed matrix degradation at invadopodia (5) and cortactin downregulation inhibited the formation of these structures (1). Cortactin is highly tyrosine phosphorylated in active invadopodia, and the level of its tyrosine phosphorylation shows a linear correlation with the concomitant matrix degradation (6). Thus tyrosine phosphorylation of cortactin appears to be a positive regulator of invasion. It remains an intriguing question how cortactin and its phosphorylation regulate invadopodia and the activity of matrix metal-loproteases. Podosomes are actin-rich structures that represent another type of matrix-cell surface interface. These structures, originally described in v-Src-transformed cells (9, 60), are composed of a core with columnar arrangement of F-actin and actin-binding proteins that protrude into the cytosol from the ventral surface. This region is surrounded by a ring containing paxillin, vinculin, and talin, through which the core is anchored to integrins (FIGURE 2C). In certain cases, these actin structures are arranged around long, intruding membrane tubules.

Podosomes are also key sites of ECM remodeling: they are believed to seal off and modify portions of the ECM under the cell. Macrophages and osteoclasts are the richest in podosomes, but many other cell types also contain these structures. Podosome formation can be induced by active Src, PKC, or PAK (10, 107), and cortactin appears to be a key component in the process, since its knockdown inhibits podosome assembly (107). Podosome genesis occurs in two phases: initially "pre-podosomal," cortactin-containing clusters occur near the end of stress fibers. Recruitment of cortactin to these precursor sites required an intact N-WASP-binding SH3 domain. Cortactin then may facilitate the assembly of columnar F-actin structures. In this second phase, more cortactin was recruited to the growing podosome, but this time in a SH3-independent but F-actin binding region-dependent manner (100). Cortactin becomes highly tyrosine phosphorylated in podosomes, but this process is not necessary for cortactin recruitment (107). Finally, cortactin has been implicated in local inhibition of contractility at the podosome by promoting the dispersion of myosin and tropomyosin at these sites (10). The mechanism and significance of this phenomenon, as well as the way whereby cortactin contributes to the podosome functions (e.g., focal bone resorption) are promising areas for future investigations. Indeed, while this paper was under review, Tehrani et al. (89) published an elegant study showing that siRNA-induced cortactin depletion in osteoclasts abolished podosome formation and bone resorption. These functions were shown to require cortactin tyrosine phosphorylation but not an intact SH3 domain.

	Cortactin at the Growth Cone and the Synapse

Top Introduction Cortactin in the Test... Cortactin at the Lamellipodia... Cortactin at Invadopodia and... Cortactin at the Growth... Cortactin at Endocytic Vesicles Cortactin at Intercellular... Cortactin at Sites of... Cortactin in the Future References

 
Intriguing new research identifies cortactin as a central player in a number of neuron-specific functions including growth cone formation (15, 23), axon guidance (path finding) (52, 53), neuronal polarization (57), dendritic spine morphogenesis (synaptogenesis) (35), differential neurotransmitter (GABA) receptor expression (15), and the modulation of voltage-gated K⁺ channels (32).

Cortactin is enriched in growth cones of developing neurons (23), and its suppression resulted in shorter processes and growth cones with enlarged filopodia (15). Its tyrosine phosphorylation at this locus has been suggested to act as a signal for repulsive growth cone turning during EphA-receptor mediated retinal axon guidance (53). Again, the picture is complex. For example, heparin-binding growth-associated molecule (HB-GAM), an important neurite outgrowth-promoting protein and spatial cue involved in neuronal path finding, induced cortactin tyrosine phosphorylation on binding to its receptor, N-syndecan. This event was associated with complex formation among N-syndecan, cortactin, and Src, and was concomitant with enhanced neurite growth (52). Thus, depending on the context, cortactin and its tyrosine phosphorylation may act as path-maintaining or repulsive signals.

It has been raised that cortactin might also be involved in neuronal polarization, the intriguing process whereby a single neurite is selected to become the axon. A recent study indicates that Fer kinase is concentrated in growth cones, and inhibition of this enzyme delays the dendrite-axon conversion (57). The two most important substrates of Fer in the growth cone are cortactin and p120 catenin [or its relative -catenin, which was shown to associate with cortactin (65)]. According to the current hypothesis, Fermediated phosphorylation might inhibit extensive actin filament branching, and this may be necessary for the rapid elongation of the forming axon. Cortactin may also play a role in regulating neurite branching: complex formation between -catenin and cortactin has been proposed to promote the extension of unbranched primary processes, whereas tyrosine phosphorylation disrupted this complex and resulted in enhanced branching in PC12 cells (65). It remains a challenge to integrate and reconcile these findings with the mechanism of axon selection.

A major step in our understanding of the role of cortactin at the synapse was the discovery that cortactin interacts with members of the Shank family, scaffold proteins of the postsynaptic density (23, 71). Shank is located under the membrane linked to both ionotropic and metabotropic glutamate receptors through various adaptor proteins (PSD-95, GKAP and Homer, respectively) (26). The proline-rich region of Shank binds to the SH3 domain of cortactin, thereby forming a multiprotein bridge between excitatory receptors and the cytoskeleton (FIGURE 2D). In addition, cortactin plays a key role in the morphogenesis of dendritic spines as verified by the findings that its down-regulation resulted in spine depletion, whereas its overexpression caused spine elongation (35). The interaction between cortactin and dynamin-3 appears to be critical for dendritic spine maturation: the presence of this complex facilitates the formation of immature dendritic filopodia, whereas its disruption (or dissociation) leads to formation of mature dendritic spines with postsynaptic densities (31). Furthermore, synaptic transmission is a dynamic regulator of cortactin distribution and therefore postsynaptic cytoskeleton organization. For example, NMDA receptor stimulation induced cortactin redistribution from the spine to the shaft (35), an effect due to Src family-mediated tyrosine phosphorylation of cortactin (41), whereas brain-derived neurotrophic factor triggered ERK-mediated serine phosphorylation of cortactin, concomitant with its translocation from the shaft to the spines (41). These fascinating findings suggest that cortactin is involved in the function-dependent remodeling of the synapse: overstimulation of NMDA receptors removes cortactin and thereby collapses dendritic spines, which may serve as a negative feedback mechanism. In contrast, neurotrophic factors use cortactin to solidify synaptic transmission. In addition, cortactin was reported to interact with the Kv1.2 K⁺ channel in a tyrosine phosphorylation-dependent manner, and this interaction may modify the acetylcholine-induced currents (32). Thus cortactin regulates ion channels and dynamically modifies synapses, which may play a role in synaptic plasticity and long-term potentiation. Indeed, evidence is accumulating that cortactin impacts on complex functions such as learning and sleep (20, 68). Clearly, the neuronal career of cortactin has only started.

	Cortactin at Endocytic Vesicles

Top Introduction Cortactin in the Test... Cortactin at the Lamellipodia... Cortactin at Invadopodia and... Cortactin at the Growth... Cortactin at Endocytic Vesicles Cortactin at Intercellular... Cortactin at Sites of... Cortactin in the Future References

 
The recognition that cortactin may play a role in endocytosis stemmed from two pioneering observations. The first was that cortactin associates with endocytic vesicles in an asymmetric manner, such that it accumulates on one pole of the vesicle, consistent with a role in actin polymerization-propelled intracellular trafficking of endosomes (45). The second finding was that cortactin binds to the proline-rich domain of dynamin, a large GTPase that pinches off the forming endocytic vesicle (67). The role of cortactin was then solidified by findings that 1) it accumulates at the clathrin-coated pits (CCPs) and 2) microinjection of anti-cortactin antibodies (12), siRNA-induced knockdown (14, 108), or the overexpression of the isolated SH3 domain inhibits endocytosis (12). Endocytosis is a complex process involving pit formation, invagination, scission, and vesicle movement away from the membrane. Recent studies shed some light on cortactin’s involvement in these particular steps. Merrifield et al. (69) studied the dynamics of individual CCPs using evanescent field microscopy and a witty technique, the pH-sensitive labeling of transferrin receptors, with which the closure and scission of CCPs can be resolved in real time. They found that cortactin starts accumulating early on at the forming pit, and its peak recruitment is coincident with scission. They propose that cortactin, by inducing local actin polymerization, promotes pit invagination, which facilitates efficient scission. Cortactin is not found in every forming pit, so it may mark a subset of CCPs. The role and mode of the cortactin-dynamin interaction is also emerging. It seems that dynamin can accumulate in an F-actin-independent manner and then recruits cortactin to the pit (14). Interestingly, cortactin engaged in actin polymerization (i.e., associated with F-actin and Arp2/3) has an eightfold higher affinity for dynamin (108). This means that dynamin will localize spots of active actin polymerization to the pit, which may be a central mechanism to coordinate invagination and subsequent fission (FIGURE 2E). Moreover, the role of the cortactin-dynamin complex is not limited to clathrin-mediated endocytosis, as inhibition of these molecules suppresses the clathrin-independent endocytosis of c cytokine receptors (80) too. Cortactin seems to affect the fate of the endocytosed receptors as well. Remarkably, its overexpression inhibited the ubiquitylation and subsequent degradation of the EGF receptor, an effect that might contribute to the invasive phenotype of cortactin-overexpressing tumor cells (92). Finally, it is worth mentioning that the dynamin-cortactin interaction is not limited to the endocytic machinery; in fact, these proteins colocalize also in the Golgi-apparatus (13), invadopodia, podosomes, and lamellipodia (75). As mentioned, dynamin facilitates the actin-nucleating effect of cortactin (82), and it has a substantial impact on lamel-lipodial kinetics and cell shape determination (55, 67). Furthermore, our ongoing studies suggest that in lamellipodia cortactin might recruit dynamin (and not the other way around as at the CCP) and that their interaction may be facilitated by tyrosine phosphorylation. Clearly, the dynamin-cortactin complex is a key component of the interplay between membrane dynamics and cytoskeleton remodeling.

	Cortactin at Intercellular Junctions

Top Introduction Cortactin in the Test... Cortactin at the Lamellipodia... Cortactin at Invadopodia and... Cortactin at the Growth... Cortactin at Endocytic Vesicles Cortactin at Intercellular... Cortactin at Sites of... Cortactin in the Future References

 
Cortactin also participates in the organization of at least two major types of intercellular contacts: TJs and adherens junctions (AJ) (FIGURE 2F). TJs are composed of transmembrane contact proteins such as the occludins and their intracellular binding partners, predominantly the members of the zonula occludens (ZO) family (87). TJs separate the apical and the basolateral membrane compartments, and the tightness of these structures determines transepithelial electrical resistance (TER) and paracellular transport. The cortactin SH3 domain has been shown to bind to the proline-rich region of ZO-1. Although little is known about the function of cortactin at the TJ, some functional studies support a positive role. Sphingosine-1 phosphate induced barrier enhancement (i.e., an increase in TER) in lung epithelial cells, which seemed to be mediated by Rac-dependent peripheral translocation of cortactin and MLCK. Downregulation of cortactin or elimination of its tyrosine phosphorylation prevented this effect (25). The barrier-enhancing role of the cortactin-MLCK complex is an intriguing finding since increased myosin-based contractility usually reduces epithelial tightness. Future studies should address whether this effect is related to ZO-1. Recently, ZO-1 was also detected in the leading edge of fibroblasts migrating in a wound, where it was suggested to initiate integrin-dependent adhesion complexes (88).

AJs are composed of cadherins, which are homotypic transmembrane adhesion molecules linked to intra-cellular plaque proteins, ß-catenin and then ß-catenin, which in turn anchor the complex to the actin skeleton (90). Recently, cortactin was found to associate with E-cadherin (epithelial cells) and N-cad-herin (fibroblasts) in nascent AJs. In epithelial cells, cortactin preferentially accumulated at the extending margins of cadherin-containing adhesive contact zones. Downregulation of cortactin or transfection with actin- or Arp2/3-binding deficient cortactin mutants, but not with tyrosine phosphorylation-incompetent mutants, inhibited contact zone extension between neighboring cells (34). These results suggest that cortactin participates in the biogenesis of epithelial AJs, presumably by regulating peripheral actin assembly, and thus membrane dynamics, necessary for the interaction of contact-forming cells (2). In fibroblast, N-cadherin engagement initiated transient Rac-dependent cortactin recruitment to the nascent contacts along with Fer kinase-mediated cortactin phosphorylation at this locus. Using N-cadherin-covered beads and shear wash-off assays, we showed that both the presence of cortactin and its tyrosine phosphorylation are critical for providing adhesion strength for the newly formed contacts (27, 28). Fer-mediated cortactin phosphorylation increased N-cad-herin mobility, which may be required for N-cadherin clustering and contact zone extension. These findings render cortactin a key regulator of AJ formation and adhesion strength. In addition, cortactin may regulate the permeability and dynamics of mature AJs as well, since downregulation of cortactin in endothelial cells impaired the transmigration of polymorphonulear leukocyets through the monolayer (106).

	Cortactin at Sites of Cell-Pathogen Interactions

Top Introduction Cortactin in the Test... Cortactin at the Lamellipodia... Cortactin at Invadopodia and... Cortactin at the Growth... Cortactin at Endocytic Vesicles Cortactin at Intercellular... Cortactin at Sites of... Cortactin in the Future References

 
Cortactin has also emerged as a common target of pathogen-host cell interactions. Depending on the particular microbe, cortactin has been implicated in adhesion (e.g., pedestal formation by enteropathogenic an enterohemorrhagic Esherichia coli), invasion (Shigella, Neisseria, Chlamydia, Rickettsia, Staphylococcus, Crytosporodium), intracellular movement (actin polymerization-propelled motility, using actin comet tails by Listeria, Shigella, and vaccinia virus), and cell scattering (Helicobacter). All these processes harness the actin cytoskeleton of the host in various ways (86). Intriguingly the effect on tyrosine phosphorylation is pathogen dependent, with robust increase (e.g., Shigella), no change (e.g., Chlamydia), or decrease (Helicobacter). Details of this rich and important topic go beyond the scope of the present paper, so the interested reader is referred to a recent excellent review (85).

	Cortactin in the Future

Top Introduction Cortactin in the Test... Cortactin at the Lamellipodia... Cortactin at Invadopodia and... Cortactin at the Growth... Cortactin at Endocytic Vesicles Cortactin at Intercellular... Cortactin at Sites of... Cortactin in the Future References

 
What can then be, if not the Holy Grail, at least the unifying principle underlying this wide diversity of potential functions, extending from cell migration/invasion through synaptic plasticity to intercellular contacts and more? Although only the future can provide a better insight, it seems likely that cortactin is one of those important molecular integrators that participate in the conversion of external (ligand-induced or mechanical) cues to appropriate membrane responses by organizing the cytoskeleton to execute the "desired" membrane remodeling. Progress in the following years is likely to solidify the link between the biochemistry and the physiology of cortactin. We hope to learn the molecular details whereby cortactin regulates cell migration, controls proteolysis during metastasis, and modifies intercellular contacts. We also hope to learn what exactly its tyrosine phosphorylation is doing. Moreover, cortactin will teach us about fundamental relationships between processes that today we view as separate entities. Thus it will help us to address the link and coordination between endo- or exocytosis and lamellipodial dynamics, or between cell migration and intercellular contact formation. There is little doubt that the gray eminence will continue to intrigue us.

	Acknowledgments

 
We are indebted to Dr. Katalin Szászi for critical reading of the manuscript.

L. I. Cosen-Binker was supported by a Premier’s Research Excellence Award to A. Kapus.

	References

Top Introduction Cortactin in the Test... Cortactin at the Lamellipodia... Cortactin at Invadopodia and... Cortactin at the Growth... Cortactin at Endocytic Vesicles Cortactin at Intercellular... Cortactin at Sites of... Cortactin in the Future References

 

1. Artym VV, Zhang Y, Seillier-Moiseiwitsch F, Yamada KM, and Mueller SC. Dynamic interactions of cortactin and membrane type 1 matrix metalloproteinase at invadopodia: defining the stages of invadopodia formation and function. Cancer Res 66: 3034–3043, 2006.[Abstract/Free Full Text]
2. Bershadsky A. Magic touch: how does cell-cell adhesion trigger actin assembly? Trends Cell Biol 14: 589–593, 2004.[CrossRef][ISI][Medline]
3. Birukov KG, Birukova AA, Dudek SM, Verin AD, Crow MT, Zhan X, DePaola N, and Garcia JG. Shear stress-mediated cytoskeletal remodeling and cortactin translocation in pulmonary endothelial cells. Am J Respir Cell Mol Biol 26: 453–464, 2002.[Abstract/Free Full Text]
4. Borisy GG and Svitkina TM. Actin machinery: pushing the envelope. Curr Opin Cell Biol 12: 104–112, 2000.[CrossRef][ISI][Medline]
5. Bowden ET, Barth M, Thomas D, Glazer RI, and Mueller SC. An invasion-related complex of cortactin, paxillin and PKCmu associates with invadopodia at sites of extracellular matrix degradation. Oncogene 18: 4440–4449, 1999.[CrossRef][ISI][Medline]
6. Bowden ET, Onikoyi E, Slack R, Myoui A, Yoneda T, Yamada KM, and Mueller SC. Colocalization of cortactin and phosphotyrosine identifies active invadopodia in human breast cancer cells. Exp Cell Res 312: 1240–1253, 2006.[CrossRef][ISI][Medline]
7. Bringuier PP, Tamimi Y, Schuuring E, and Schalken J. Expression of cyclin D1 and EMS1 in bladder tumours; relationship with chromosome 11q13 amplification. Oncogene 12: 1747–1753, 1996.[ISI][Medline]
8. Bryce NS, Clark ES, Leysath JL, Currie JD, Webb DJ, and Weaver AM. Cortactin promotes cell motility by enhancing lamellipodial persistence. Curr Biol 15: 1276–1285, 2005.[CrossRef][ISI][Medline]
9. Buccione R, Orth JD, and McNiven MA. Foot and mouth: podosomes, invadopodia and circular dorsal ruffles. Nat Rev Mol Cell Biol 5: 647–657, 2004.[CrossRef][ISI][Medline]
10. Burgstaller G and Gimona M. Actin cytoskeleton remodelling via local inhibition of contractility at discrete microdomains. J Cell Sci 117: 223–231, 2004.[Abstract/Free Full Text]
11. Campbell DH, Sutherland RL, and Daly RJ. Signaling pathways and structural domains required for phosphorylation of EMS1/cortactin. Cancer Res 59: 5376–5385, 1999.[Abstract/Free Full Text]
12. Cao H, Orth JD, Chen J, Weller SG, Heuser JE, and McNiven MA. Cortactin is a component of clathrin-coated pits and participates in receptor-mediated endocytosis. Mol Cell Biol 23: 2162–2170, 2003.[Abstract/Free Full Text]
13. Cao H, Weller S, Orth JD, Chen J, Huang B, Chen JL, Stamnes M, and McNiven MA. Actin and Arf1-dependent recruitment of a cortactindynamin complex to the Golgi regulates post-Golgi transport. Nat Cell Biol 7: 483–492, 2005.[CrossRef][ISI][Medline]
14. Chen L, Wang ZW, Zhu JW, and Zhan X. Roles of cortactin, an actin polymerization mediator, in cell endocytosis. Acta Biochim Biophys Sin (Shanghai) 38: 95–103, 2006.[Medline]
15. Cheng Y, Leung S, and Mangoura D. Transient suppression of cortactin ectopically induces large telencephalic neurons towards a GABAergic phenotype. J Cell Sci 113: 3161–3172, 2000.[Abstract]
16. Chuma M, Sakamoto M, Yasuda J, Fujii G, Nakanishi K, Tsuchiya A, Ohta T, Asaka M, and Hirohashi S. Overexpression of cortactin is involved in motility and metastasis of hepatocellular carcinoma. J Hepatol 41: 629–636, 2004.[CrossRef][ISI][Medline]
17. Cosen-Binker L, Fan L, Szaszi K, Di Ciano-Oliveira C, and Kapus A. Cortactin is indispensable for EGF-induced rapid lamellipod extension in mammary tumor cells. Mol Biol Cell 15: A147, 141a, 2004.
18. Crostella L, Lidder S, Williams R, and Skouteris GG. Hepatocyte growth factor/scatter factor-induces phosphorylation of cortactin in A431 cells in a Src kinase-independent manner. Oncogene 20: 3735–3745, 2001.[CrossRef][ISI][Medline]
19. Daly RJ. Cortactin signalling and dynamic actin networks. Biochem J 382: 13–25, 2004.[CrossRef][ISI][Medline]
20. Davis CJ, Meighan PC, Taishi P, Krueger JM, Harding JW, and Wright JW. REM sleep deprivation attenuates actin-binding protein cortactin: a link between sleep and hippocampal plasticity. Neurosci Lett 400: 191–196, 2006.[CrossRef][ISI][Medline]
21. Destaing O, Saltel F, Geminard JC, Jurdic P, and Bard F. Podosomes display actin turnover and dynamic self-organization in osteoclasts expressing actin-green fluorescent protein. Mol Biol Cell 14: 407–416, 2003.[Abstract/Free Full Text]
22. Di Ciano C, Nie Z, Szaszi K, Lewis A, Uruno T, Zhan X, Rotstein OD, Mak A, and Kapus A. Osmotic stress-induced remodeling of the cortical cytoskeleton. Am J Physiol Cell Physiol 283: C850–C865, 2002.[Abstract/Free Full Text]
23. Du Y, Weed SA, Xiong WC, Marshall TD, and Parsons JT. Identification of a novel cortactin SH3 domain-binding protein and its localization to growth cones of cultured neurons. Mol Cell Biol 18: 5838–5851, 1998.[Abstract/Free Full Text]
24. Dudek SM, Birukov KG, Zhan X, and Garcia JG. Novel interaction of cortactin with endothelial cell myosin light chain kinase. Biochem Biophys Res Commun 298: 511–519, 2002.[CrossRef][ISI][Medline]
25. Dudek SM, Jacobson JR, Chiang ET, Birukov KG, Wang P, Zhan X, and Garcia JG. Pulmonary endothelial cell barrier enhancement by sphingosine 1-phosphate: roles for cortactin and myosin light chain kinase. J Biol Chem 279: 24692–24700, 2004.[Abstract/Free Full Text]
26. Ehlers MD. Synapse structure: glutamate receptors connected by the shanks. Curr Biol 9: 848–850, 1999.
27. El Sayegh TY, Arora PD, Fan L, Laschinger CA, Greer PA, McCulloch CA, and Kapus A. Phosphorylation of N-cadherin-associated cortactin by Fer kinase regulates N-cadherin mobility and intercellular adhesion strength. Mol Biol Cell 16: 5514–5527, 2005.[Abstract/Free Full Text]
28. El Sayegh TY, Arora PD, Laschinger CA, Lee W, Morrison C, Overall CM, Kapus A, and McCulloch CA. Cortactin associates with N-cadherin adhesions and mediates intercellular adhesion strengthening in fibroblasts. J Cell Sci 117: 5117–5131, 2004.[Abstract/Free Full Text]
29. Fan L, Di Ciano-Oliveira C, Weed SA, Craig AW, Greer PA, Rotstein OD, and Kapus A. Actin depolymerization-induced tyrosine phosphorylation of cortactin: the role of Fer kinase. Biochem J 380: 581–591, 2004.[CrossRef][ISI][Medline]
30. Gallet C, Rosa JP, Habib A, Lebret M, Levy-Toledano S, and Maclouf J. Tyrosine phosphorylation of cortactin associated with Syk accompanies thromboxane analogue-induced platelet shape change. J Biol Chem 274: 23610–23616, 1999.[Abstract/Free Full Text]
31. Gray NW, Kruchten AE, Chen J, and McNiven MA. A dynamin-3 spliced variant modulates the actin/cortactin-dependent morphogenesis of dendritic spines. J Cell Sci 118: 1279–1290, 2005.[Abstract/Free Full Text]
32. Hattan D, Nesti E, Cachero TG, and Morielli AD. Tyrosine phosphorylation of Kv1.2 modulates its interaction with the actin-binding protein cortactin. J Biol Chem 277: 38596–38606, 2002.[Abstract/Free Full Text]
33. Head JA, Jiang D, Li M, Zorn LJ, Schaefer EM, Parsons JT, and Weed SA. Cortactin tyrosine phosphorylation requires Rac1 activity and association with the cortical actin cytoskeleton. Mol Biol Cell 14: 3216–3229, 2003.[Abstract/Free Full Text]
34. Helwani FM, Kovacs EM, Paterson AD, Verma S, Ali RG, Fanning AS, Weed SA, and Yap AS. Cortactin is necessary for E-cadherin-mediated contact formation and actin reorganization. J Cell Biol 164: 899–910, 2004.[Abstract/Free Full Text]
35. Hering H and Sheng M. Activity-dependent redistribution and essential role of cortactin in dendritic spine morphogenesis. J Neurosci 23: 11759–11769, 2003.[Abstract/Free Full Text]
36. Higgs HN and Pollard TD. Regulation of actin filament network formation through ARP2/3 complex: activation by a diverse array of proteins. Annu Rev Biochem 70: 649–676, 2001.[CrossRef][ISI][Medline]
37. Hou P, Estrada L, Kinley AW, Parsons JT, Vojtek AB, and Gorski JL. Fgd1, the Cdc42 GEF responsible for Faciogenital Dysplasia, directly interacts with cortactin and mAbp1 to modulate cell shape. Hum Mol Genet 12: 1981–1993, 2003.[Abstract/Free Full Text]
38. Huang C, Liu J, Haudenschild CC, and Zhan X. The role of tyrosine phosphorylation of cortactin in the locomotion of endothelial cells. J Biol Chem 273: 25770–25776, 1998.[Abstract/Free Full Text]
39. Huang C, Ni Y, Wang T, Gao Y, Haudenschild CC, and Zhan X. Down-regulation of the filamentous actin cross-linking activity of cortactin by Src-mediated tyrosine phosphorylation. J Biol Chem 272: 13911–13915, 1997.[Abstract/Free Full Text]
40. Huang C, Tandon NN, Greco NJ, Ni Y, Wang T, and Zhan X. Proteolysis of platelet cortactin by calpain. J Biol Chem 272: 19248–19252, 1997.[Abstract/Free Full Text]
41. Iki J, Inoue A, Bito H, and Okabe S. Bi-directional regulation of postsynaptic cortactin distribution by BDNF and NMDA receptor activity. Eur J Neurosci 22: 2985–2994, 2005.[CrossRef][ISI][Medline]
42. Illes A, Enyedi B, Tamas P, Balazs A, Bogel G, and Buday L. Inducible phosphorylation of cortactin is not necessary for cortactin-mediated actin polymerisation. Cell Signal 18: 830–840, 2006.[CrossRef][ISI][Medline]
43. Illes A, Enyedi B, Tamas P, Balazs A, Bogel G, Melinda Lukacs, and Buday L. Cortactin is required for integrin-mediated cell spreading. Immunol Lett 104: 124–130, 2006.[CrossRef][ISI][Medline]
44. Imaoka T, Horseman ND, Lockefeer JA, Mori T, and Matsuda M. Cortactin-binding protein 90 (CBP90) expression in the mouse mammary glands during prolactin-induced lobuloalveolar development. Zoolog Sci 19: 443–448, 2002.[CrossRef][ISI][Medline]
45. Kaksonen M, Peng HB, and Rauvala H. Association of cortactin with dynamic actin in lamellipodia and on endosomal vesicles. J Cell Sci 113: 4421–4426, 2000.[Abstract]
46. Kapus A, Di Ciano C, Sun J, Zhan X, Kim L, Wong TW, and Rotstein OD. 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 275: 32289–32298, 2000.[Abstract/Free Full Text]
47. Kapus A, Szaszi K, Sun J, Rizoli S, and Rotstein OD. Cell shrinkage regulates Src kinases and induces tyrosine phosphorylation of cortactin, independent of the osmotic regulation of Na⁺/H⁺ exchangers. J Biol Chem 274: 8093–8102, 1999.[Abstract/Free Full Text]
48. Kempiak SJ, Yamaguchi H, Sarmiento C, Sidani M, Ghosh M, Eddy RJ, Desmarais V, Way M, Condeelis J, and Segall JE. A neural Wiskott-Aldrich Syndrome protein-mediated pathway for localized activation of actin polymerization that is regulated by cortactin. J Biol Chem 280: 5836–5842, 2005.[Abstract/Free Full Text]
49. Kim K, Hou P, Gorski JL, and Cooper JA. Effect of Fgd1 on cortactin in Arp2/3 complex-mediated actin assembly. Biochemistry 43: 2422–2427, 2004.[CrossRef][Medline]
50. Kim L and Wong TW. Growth factor-dependent phosphorylation of the actin-binding protein cortactin is mediated by the cytoplasmic tyrosine kinase FER. J Biol Chem 273: 23542–23548, 1998.[Abstract/Free Full Text]
51. Kinley AW, Weed SA, Weaver AM, Karginov AV, Bissonette E, Cooper JA, and Parsons JT. Cortactin interacts with WIP in regulating Arp2/3 activation and membrane protrusion. Curr Biol 13: 384–393, 2003.[CrossRef][ISI][Medline]
52. Kinnunen T, Kaksonen M, Saarinen J, Kalkkinen N, Peng HB, and Rauvala H. Cortactin-Src kinase signaling pathway is involved in N-syndecan-dependent neurite outgrowth. J Biol Chem 273: 10702–10708, 1998.[Abstract/Free Full Text]
53. Knoll B and Drescher U. Src family kinases are involved in EphA receptor-mediated retinal axon guidance. J Neurosci 24: 6248–6257, 2004.[Abstract/Free Full Text]
54. Kowalski JR, Egile C, Gil S, Snapper SB, Li R, and Thomas SM. Cortactin regulates cell migration through activation of N-WASP. J Cell Sci 118: 79–87, 2005.[Abstract/Free Full Text]
55. Krueger EW, Orth JD, Cao H, and McNiven MA. A dynamin-cortactin-Arp2/3 complex mediates actin reorganization in growth factor-stimulated cells. Mol Biol Cell 14: 1085–1096, 2003.[Abstract/Free Full Text]
56. Lee JF, Ozaki H, Zhan X, Wang E, Hla T, and Lee MJ. Sphingosine-1-phosphate signaling regulates lamellipodia localization of cortactin complexes in endothelial cells. Histochem Cell Biol: 1–8, 2006.
57. Lee SH. Interaction of nonreceptor tyrosine-kinase Fer and p120 catenin is involved in neuronal polarization. Mol Cells 20: 256–262, 2005.[ISI][Medline]
58. Li Y, Tondravi M, Liu J, Smith E, Haudenschild CC, Kaczmarek M, and Zhan X. Cortactin potentiates bone metastasis of breast cancer cells. Cancer Res 61: 6906–6911, 2001.[Abstract/Free Full Text]
59. Lin J, Liu J, Wang Y, Zhu J, Zhou K, Smith N, and Zhan X. Differential regulation of cortactin and N-WASP-mediated actin polymerization by missing in metastasis (MIM) protein. Oncogene 24: 2059–2066, 2005.[CrossRef][ISI][Medline]
60. Linder S and Aepfelbacher M. Podosomes: adhesion hot-spots of invasive cells. Trends Cell Biol 13: 376–385, 2003.[CrossRef][ISI][Medline]
61. Liu J, Huang C, and Zhan X. Src is required for cell migration and shape changes induced by fibroblast growth factor 1. Oncogene 18: 6700–6706, 1999.[CrossRef][ISI][Medline]
62. Lua BL and Low BC. Cortactin phosphorylation as a switch for actin cytoskeletal network and cell dynamics control. FEBS Lett 579: 577–585, 2005.[CrossRef][ISI][Medline]
63. Lynch DK, Winata SC, Lyons RJ, Hughes WE, Lehrbach GM, Wasinger V, Corthals G, Cordwell S, and Daly RJ. A cortactin-CD2-associated protein (CD2AP) complex provides a novel link between epidermal growth factor receptor endocytosis and the actin cytoskeleton. J Biol Chem 278: 21805–21813, 2003.[Abstract/Free Full Text]
64. Martinez-Quiles N, Ho HY, Kirschner MW, Ramesh N, and 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 24: 5269–5280, 2004.[Abstract/Free Full Text]
65. Martinez MC, Ochiishi T, Majewski M, and Kosik KS. Dual regulation of neuronal morphogenesis by a delta-catenin-cortactin complex and Rho. J Cell Biol 162: 99–111, 2003.[Abstract/Free Full Text]
66. McNiven MA, Baldassarre M, and Buccione R. The role of dynamin in the assembly and function of podosomes and invadopodia. Front Biosci 9: 1944–1953, 2004.[ISI][Medline]
67. McNiven MA, Kim L, Krueger EW, Orth JD, Cao H, and Wong TW. Regulated interactions between dynamin and the actin-binding protein cortactin modulate cell shape. J Cell Biol 151: 187–198, 2000.[Abstract/Free Full Text]
68. Meighan SE, Meighan PC, Choudhury P, Davis CJ, Olson ML, Zornes PA, Wright JW, and Harding JW. Effects of extracellular matrix-degrading proteases matrix metalloproteinases 3 and 9 on spatial learning and synaptic plasticity. J Neurochem 96: 1227–1241, 2006.[CrossRef][ISI][Medline]
69. Merrifield CJ, Perrais D, and Zenisek D. Coupling between clathrin-coated-pit invagination, cortactin recruitment, and membrane scission observed in live cells. Cell 121: 593–606, 2005.[CrossRef][ISI][Medline]
70. Mizutani K, Miki H, He H, Maruta H, and Takenawa T. Essential role of neural Wiskott-Aldrich syndrome protein in podosome formation and degradation of extracellular matrix in src-transformed fibroblasts. Cancer Res 62: 669–674, 2002.[Abstract/Free Full Text]
71. Naisbitt S, Kim E, Tu JC, Xiao B, Sala C, Valtschanoff J, Weinberg RJ, Worley PF, and Sheng M. Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin. Neuron 23: 569–582, 1999.[CrossRef][ISI][Medline]
72. Ohoka Y and Takai Y. Isolation and characterization of cortactin isoforms and a novel cortactin-binding protein, CBP90. Genes Cells 3: 603–612, 1998.[Abstract]
73. Okamura H and Resh MD. p80/85 cortactin associates with the Src SH2 domain and colocalizes with v-Src in transformed cells. J Biol Chem 270: 26613–26618, 1995.[Abstract/Free Full Text]
74. Ormandy CJ, Musgrove EA, Hui R, Daly RJ, and Sutherland RL. Cyclin D1, EMS1 and 11q13 amplification in breast cancer. Breast Cancer Res Treat 78: 323–335, 2003.[CrossRef][ISI][Medline]
75. Orth JD and McNiven MA. Dynamin at the actin-membrane interface. Curr Opin Cell Biol 15: 31–39, 2003.[CrossRef][ISI][Medline]
76. Pant K, Chereau D, Hatch V, Dominguez R, and Lehman W. Cortactin binding to F-actin revealed by electron microscopy and 3D reconstruction. J Mol Biol 359: 840–847, 2006.[CrossRef][ISI][Medline]
77. Patel AM, Incognito LS, Schechter GL, Wasilenko WJ, and Somers KD. Amplification and expression of EMS-1 (cortactin) in head and neck squamous cell carcinoma cell lines. Oncogene 12: 31–35, 1996.[ISI][Medline]
78. Patel AS, Schechter GL, Wasilenko WJ, and Somers KD. Overexpression of EMS1/cortactin in NIH3T3 fibroblasts causes increased cell motility and invasion in vitro. Oncogene 16: 3227–3232, 1998.[CrossRef][ISI][Medline]
79. Perrin BJ, Amann KJ, and Huttenlocher A. Proteolysis of cortactin by calpain regulates membrane protrusion during cell migration. Mol Biol Cell 17: 239–250, 2006.[Abstract/Free Full Text]
80. Sauvonnet N, Dujeancourt A, and Dautry-Varsat A. Cortactin and dynamin are required for the clathrin-independent endocytosis of gammac cytokine receptor. J Cell Biol 168: 155–163, 2005.[Abstract/Free Full Text]
81. Schafer DA. Coupling actin dynamics and membrane dynamics during endocytosis. Curr Opin Cell Biol 14: 76–81, 2002.[CrossRef]