Cortactin Promotes Cell Motility by Enhancing Lamellipodial Persistence

Bryce, Nicole S.; Clark, Emily; Leysath, Ja’Mes L.; Currie, Joshua D.; Webb, Donna J.; Weaver, Alissa M.

doi:10.1016/j.cub.2005.06.043

Cited by 257 publications

(332 citation statements)

References 40 publications

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“…Moreover, cortactin potentiates bone metastasis of breast cancer cells in nude mice (Li et al, 2001). Lastly, recent findings demonstrate that fibrosarcoma cells deficient in cortactin have impaired cell migration and invasion, underscoring the role of cortactin in cell motility (Bryce et al, 2005). Histone deacetylases (HDACs) are enzymes that catalyse the removal of the acetyl moieties from the e-amino group of the lysine residues in histone and nonhistone proteins (Cress and Seto, 2000;Grozinger and Schreiber, 2002;Blander and Guarente, 2004;Gregoretti et al, 2004;Glozak et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Deacetylation of cortactin by SIRT1 promotes cell migration

et al. 2008

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Cortactin binds F-actin and promotes cell migration. We showed earlier that cortactin is acetylated. Here, we identify SIRT1 (a class III histone deacetylase) as a cortactin deacetylase and p300 as a cortactin acetylase. We show that SIRT1 deacetylates cortactin in vivo and in vitro and that the SIRT1 inhibitor EX-527 increases amounts of acetylated cortactin in ovarian cancer cells. We also show that p300 acetylates cortactin in vivo and that cells lacking or depleted of p300 express lessacetylated cortactin than do control cells. Deletion analysis mapped the SIRT1-binding domain of cortactin to its repeat region, which also binds F-actin. Mouse embryo fibroblasts (MEFs) lacking sir2a (the mouse homolog of SIRT1) migrated more slowly than did wildtype cells. The expression of SIRT1 in sir2a-null cells restored migratory capacity, as did expression of a deacetylation-mimetic mutant of cortactin. SIRT1 and cortactin were more abundant in breast tumor tissue than in their normal counterparts, whereas SIRT1 expression inversely correlates with the ratio of acetylation cortactin versus total cortactin. These data suggest that deacetylation of cortactin is associated with high levels of SIRT1 and tumorigenesis. Finally, breast and ovarian cancer cell lines expressing an acetylation mimetic mutant of cortactin are less motile than that of control cells, whereas cells expressing the deacetylation mimetic mutant of cortactin migrate faster than that of control cells in Transwell migration assays. In summary, our results suggest that cortactin is a novel substrate for SIRT1 and p300 and, for the first time, a possible role for SIRT1 in cell motility through deacetylation of cortactin.

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Section: Introductionmentioning

confidence: 99%

Deacetylation of cortactin by SIRT1 promotes cell migration

et al. 2008

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“…One such gene encodes a protein similar to cortactin-binding protein 2. The orthologous cortactin-binding protein 90 associates with cortactin, a multidomain scaffolding protein involved in actin polymerization (38). In the rat, the known expression of cortactinbinding protein 90 is restricted to the brain (39).…”

Section: Resultsmentioning

confidence: 99%

Analysis and functional evaluation of the hair-cell transcriptome

McDermott

Baucom

Hudspeth

2007

Proc. Natl. Acad. Sci. U.S.A.

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An understanding of the molecular bases of the morphogenesis, organization, and functioning of hair cells requires that the genes expressed in these cells be identified and their functions ascertained. After purifying zebrafish hair cells and detecting mRNAs with oligonucleotide microarrays, we developed a subtractive strategy that identified 1,037 hair cell-expressed genes whose cognate proteins subserve functions including membrane transport, synaptic transmission, transcriptional control, cellular adhesion and signal transduction, and cytoskeletal organization. To assess the validity of the subtracted hair-cell data set, we verified the presence of 11 transcripts in inner-ear tissue. Functional evaluation of two genes from the subtracted data set revealed their importance in hair bundles: zebrafish larvae bearing the seahorse and ift 172 mutations display specific kinociliary defects. Moreover, a search for candidate genes that underlie heritable deafness identified a human ortholog of a zebrafish hair-cell gene whose map location is bracketed by the markers of a deafness locus.auditory system ͉ balance ͉ hearing ͉ vestibular system ͉ zebrafish

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“…Cortactin-S298A Enhances Polarized Cell Migration-Because we have already shown that the activity status of PKD affects Panc89 as well as breast cancer cell motility (1-3) and cortactin has been published to affect cell migration (16) we were prompted to test whether cortactin or its respective S298A mutation would alter migration of Panc89 cells toward a chemotactic serum gradient in Transwell migration assays. In line with Ref.…”

Section: Pkd-mediated Phosphorylation Of Cortactin At Sermentioning

confidence: 99%

“…Cortactin was further shown to co-localize with proteins of the Arp2/3 complex at sites of actin polymerization within lamellipodia (12). It synergistically accelerates Arp complex-mediated actin polymerization (15) and has been shown to promote cell migration by enhancing lamellipodia persistence (16). We have thus investigated a role of PKD as an upstream regulator of cortactin and its function in actin organization as well as cell migration.…”

mentioning

confidence: 99%

Protein Kinase D Controls Actin Polymerization and Cell Motility through Phosphorylation of Cortactin

Eiseler

Haußer

Kimpe

et al. 2010

Journal of Biological Chemistry

125

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We here identify protein kinase D (PKD) as an upstream regulator of the F-actin-binding protein cortactin and the Arp actin polymerization machinery. PKD phosphorylates cortactin in vitro and in vivo at serine 298 thereby generating a 14-3-3 binding motif. In vitro, a phosphorylation-deficient cortactin-S298A protein accelerated VCA-Arp-cortactin-mediated synergistic actin polymerization and showed reduced F-actin binding, indicative of enhanced turnover of nucleation complexes. In vivo, cortactin co-localized with the nucleation promoting factor WAVE2, essential for lamellipodia extension, in the actin polymerization zone in Heregulin-treated MCF-7 cells. Using a 3-dye FRET-based approach we further demonstrate that WAVE2-Arp and cortactin prominently interact at these structures. Accordingly, cortactin-S298A significantly enhanced lamellipodia extension and directed cell migration. Our data thus unravel a previously unrecognized mechanism by which PKD controls cancer cell motility.The mechanistic elucidation of signaling pathways regulating dynamic actin remodeling processes in migrating cells is pivotal to a comprehensive understanding of cancer cell metastasis. Protein kinase D (PKD) 2 has recently been identified as a vital upstream regulator of polarized cell motility and F-actin organization (1-4). PKD localizes to sites of dynamic actin remodeling (1). The kinase activity is essential for the control of directed cell motility (1, 2), whereby active PKD1 inhibited, whereas kinase-inactive PKD1KD strongly enhanced motility and invasiveness (1-4). Mechanistically, a key role for PKD1 in controlling the activity of the ubiquitous F-actin depolymerizing-and severing factor cofilin via slingshot1L (SSH1L) cofilin phosphatase has been demonstrated. The activity of SSH1L is mainly regulated by its binding to filamentous actin (F-actin), which has been shown to strongly enhance its activity (5, 6). Phosphorylation of SSH1L at Ser 978 by active PKD1, e.g. downstream of RhoA or oxidative stress, generates a 14-3-3 binding motif within an important F-actin binding region, thus resulting in the sequestration of SSH1L away from dynamic actin structures, reducing SSH1 activity and active non-S3-phosphorylated cofilin levels (2). By severing actin filaments, cofilin increases both the availability of G-actin monomers as well as the number of "barbed ends" for polymerization (7). Furthermore, severed filaments are the preferred substrate for dendritic nucleation by the Arp complex (8, 9). Localized induction of actin polymerization and the formation of branched actin networks constitute the basis for membrane protrusion and cell motility (2, 10, 11). In line with an upstream regulatory role in the control of these processes, PKD1 and -2 are also capable of binding to F-actin in vitro (1). In the case of PKD1, in vivo F-actin binding has been demonstrated as well, which most likely facilitates an interaction with actin regulatory proteins such as SSH1L (2). We now have identified a second key regulatory signaling pathway ...

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Cortactin Promotes Cell Motility by Enhancing Lamellipodial Persistence

Abstract: Cortactin enhances lamellipodial persistence, at least in part through regulation of Arp2/3 complex. The presence of cortactin also enhances the rate of new adhesion formation in lamellipodia. In vivo, these functions may be important during directed cell motility.

Cited by 257 publications

References 40 publications

Deacetylation of cortactin by SIRT1 promotes cell migration

Deacetylation of cortactin by SIRT1 promotes cell migration

Analysis and functional evaluation of the hair-cell transcriptome

Protein Kinase D Controls Actin Polymerization and Cell Motility through Phosphorylation of Cortactin

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