Cofilin determines the migration behavior and turning frequency of metastatic cancer cells

Sidani, Mazen; Wessels, Deborah; Mouneimne, Ghassan; Ghosh, Mousumi; Goswami, Sumanta; Sarmiento, Corina; Wang, Weigang; Kuhl, Spencer; El‐Sibai, Mirvat; Backer, Jonathan M.; Eddy, Robert J.; Soll, David R.; Condeelis, John S.

doi:10.1083/jcb.200707009

Cited by 172 publications

(193 citation statements)

References 51 publications

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“…This effect was similar to that of cells lacking Coronin 1B, an F-actin-binding protein that is localized to the leading edge of migrating fibroblasts (35). Cells that lacked PLEKHG3 had a longer shape, similar to that observed in cells lacking other well-known proteins, such as Cofilin (36) or WISp39 (37), that are localized to the leading edge. There was no significant difference in the actin structures of the H9 and PLEKHG3 −/− cells.…”

Section: Discussionsupporting

confidence: 61%

“…There was no significant difference in the actin structures of the H9 and PLEKHG3 −/− cells. The elongated cell shape in the PLEKHG3 −/− cells might result from the enrichment of myosin II at the trailing edge of cells, which leads to antagonistic protrusion activity (38,39), or from an asymmetric localization of the Arp2/3 complex to the leading edge of the elongated cell (36). Here, we observed that PA-Rac1 led to the formation of lamellipodia, and PLEKHG3 was detected in the newly formed protrusion area on a characteristic time scale of ∼30 s. Closer observation showed the recruitment of PLEKHG3 at the newly formed actin filaments at the leading edge.…”

Section: Discussionmentioning

confidence: 99%

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PLEKHG3 enhances polarized cell migration by activating actin filaments at the cell front

Nguyen

Park

et al. 2016

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

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Cells migrate by directing Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division control protein 42 (Cdc42) activities and by polymerizing actin toward the leading edge of the cell. Previous studies have proposed that this polarization process requires a local positive feedback in the leading edge involving Rac small GTPase and actin polymerization with PI3K likely playing a coordinating role. Here, we show that the pleckstrin homology and RhoGEF domain containing G3 (PLEKHG3) is a PI3K-regulated Rho guanine nucleotide exchange factor (RhoGEF) for Rac1 and Cdc42 that selectively binds to newly polymerized actin at the leading edge of migrating fibroblasts. Optogenetic inactivation of PLEKHG3 showed that PLEKHG3 is indispensable both for inducing and for maintaining cell polarity. By selectively binding to newly polymerized actin, PLEKHG3 promotes local Rac1/Cdc42 activation to induce more local actin polymerization, which in turn promotes the recruitment of more PLEKHG3 to induce and maintain cell front. Thus, autocatalytic reinforcement of PLEKHG3 localization to the leading edge of the cell provides a molecular basis for the proposed positive feedback loop that is required for cell polarization and directed migration.PLEKHG3 | cell polarity | F-actin binding | positive feedback | PI3K

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

PLEKHG3 enhances polarized cell migration by activating actin filaments at the cell front

Nguyen

Park

et al. 2016

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

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“…Cofilin regulates actin dynamics by severing actin filaments and sequestering the actin monomer from the pointed end of actin filaments. Though, once phosphorylated by LIMKs, cofilin can no longer bind to actin, resulting in increase of actin polymers, actin stress fiber formation and a reduction in cell mobility (Arber et al, 1998;Sidani et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

The Cdk inhibitor p57Kip2 controls LIM-kinase 1 activity and regulates actin cytoskeleton dynamics

Vlachos

Joseph

2009

Oncogene

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“…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).…”

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

121

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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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Cofilin determines the migration behavior and turning frequency of metastatic cancer cells

Cited by 172 publications

References 51 publications

PLEKHG3 enhances polarized cell migration by activating actin filaments at the cell front

PLEKHG3 enhances polarized cell migration by activating actin filaments at the cell front

The Cdk inhibitor p57Kip2 controls LIM-kinase 1 activity and regulates actin cytoskeleton dynamics

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

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