Protein kinase D1 regulates cofilin-mediated F-actin reorganization and cell motility through slingshot

Eiseler, Tim; Döppler, Heike; Yan, Irene K.; Kitatani, Kanae; Mizuno, Kensaku; Störz, Peter

doi:10.1038/ncb1861

Cited by 227 publications

(335 citation statements)

References 45 publications

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“…The activity of cofilin is controlled by phosphorylation and dephosphorylation on serine-3 of cofilin by LIMK and Slingshot-1L (SSH), respectively. 14,15 Consistent with the role of RanBP9 in focal adhesion disruption, 9 cofilin levels were dramatically enhanced (Figures 7a and b), and serine-3 phosphorylated cofilin levels were reduced after RanBP9 transfection (Figure 7a). Therefore, RanBP9 significantly reduced the level of phosphocofilin per total cofilin to less than 15% of control-transfected cells (Figure 7c).…”

Section: Wt Ranbp9 Tgsupporting

confidence: 58%

Pivotal role of the RanBP9-cofilin pathway in Aβ-induced apoptosis and neurodegeneration

et al. 2012

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Neurodegeneration associated with amyloid b (Ab) peptide accumulation, synaptic loss, neuroinflammation, tauopathy, and memory impairments encompass the pathophysiological features of Alzheimer's disease (AD). We previously reported that the scaffolding protein RanBP9, which is overall increased in brains of AD patients, simultaneously promotes Ab generation and focal adhesion disruption by accelerating the endocytosis of amyloid precursor protein (APP) and b1-integrin, respectively. Here, we show that RanBP9 protein levels are increased by fourfold in FAD mutant APP transgenic mice. Accordingly, RanBP9 transgenic mice demonstrate significantly increased synapse loss, neurodegeneration, gliosis, and spatial memory deficits. RanBP9 overexpression promotes apoptosis and potentiates Ab-induced neurotoxicity independent of its capacity to promote Ab generation. Conversely, RanBP9 reduction by siRNA or gene dosage mitigates Ab-induced neurotoxicity. Importantly, RanBP9 activates/dephosphorylates cofilin, a key regulator of actin dynamics and mitochondria-mediated apoptosis, and siRNA knockdown of cofilin abolishes both Ab and RanBP9-induced apoptosis. These findings implicate the RanBP9-cofilin pathway as critical therapeutic targets not only for stemming Ab generation but also antagonizing Ab-induced neurotoxicity. Cell Death and Differentiation (2012) 19, 1413-1423; doi:10.1038/cdd.2012.14; published online 24 February 2012Alzheimer's disease (AD) is a neurodegenerative disorder characterized by accumulations of the amyloid b (Ab) -peptide and hyperphosphorylated tau in senile plaques and neurofibrillary tangles, respectively. Ab is a neurotoxic peptide derived from b-and g-secretase cleavages of the amyloid precursor protein (APP) and is thought to be a critical early player in AD pathogenesis. 1 In addition to the accumulation of Ab and tau, abnormalities in the actin cytoskeleton are detected earlier during the course of AD and other neurodegenerative diseases. 2 Indeed, it has been demonstrated that Ab can induce actin/cofilin pathology associated with hyperphosphorylated tau in primary neurons and in vivo. [3][4][5] We recently demonstrated that the scaffolding protein RanBP9 interacts with the cytoplasmic tails of LRP, APP, and BACE1, and functions as a scaffold upon which APP is brought together with BACE1 and LRP. Such interactions of RanBP9 promote the endocytosis of APP and strongly increase BACE1 cleavage of APP to generate Ab in vitro and in vivo. 6,7 Conversely, siRNA knockdown of RanBP9 reduces BACE1 cleavage of APP and Ab generation, indicating that endogenous RanBP9 normally functions in this capacity. 6 In addition, a 60-kD proteolytic fragment of RanBP9 is increased by more than sixfold in brains of AD patients, and this fragment potentiates Ab generation via BACE1 processing of APP. 8 In addition to promoting Ab generation by accelerating APP endocytosis, RanBP9 also potently disrupts integrin-dependent focal adhesion signaling and assembly by accelerating b1-integrin and LRP endocytosis. 9 In th...

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Section: Wt Ranbp9 Tgsupporting

confidence: 58%

Pivotal role of the RanBP9-cofilin pathway in Aβ-induced apoptosis and neurodegeneration

et al. 2012

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“…This may be an important goal for future therapeutics as there is emerging evidence that PKD isoforms play different roles in tumors of different origin. For example, a series of studies by Eiseler and coworkers found that PKD1 negatively regulates migration of Panc89 cells through several related mechanisms including association of PKD with F-actin and phosphorylation of cortactin and slingshot 1 (SSH1) (42)(43)(44). In addition, PKD1 expression is decreased in invasive breast cancers and expression of a constitutively active PKD1 mutant decreased the invasiveness of MDA-MB-231 breast carcinoma cells by causing a subsequent decrease in matrix metalloproteinase expression (45).…”

Section: Pkd and Tumor Angiogenesismentioning

confidence: 99%

Protein kinase D in vascular biology and angiogenesis

Evans

Zachary

2011

IUBMB Life

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SummaryThe Protein Kinase D (PKD) family comprises diacylglycerol stimulated serine/threonine protein kinases that participate in many key signaling pathways in a diverse range of cells. Recent studies show that PKD isoforms 1 and 2 play critical roles in vascular biology and angiogenesis and there has been considerable progress in determining some of the key angiogenic signaling pathways mediated by PKD in endothelial cells. Less is currently known regarding the specific roles of PKD isoforms in endothelial cells and the role of PKD in smooth muscle cells. PKD is also emerging as a potentially important mediator of tumor growth and tumor angiogenesis and there is growing interest in PKD as a novel therapeutic target in cancer.

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“…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)(2)(3)(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.…”

mentioning

confidence: 99%

“…Protein kinase D (PKD) 2 has recently been identified as a vital upstream regulator of polarized cell motility and F-actin organization (1)(2)(3)(4). PKD localizes to sites of dynamic actin remodeling (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

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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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Protein kinase D1 regulates cofilin-mediated F-actin reorganization and cell motility through slingshot

Cited by 227 publications

References 45 publications

Pivotal role of the RanBP9-cofilin pathway in Aβ-induced apoptosis and neurodegeneration

Pivotal role of the RanBP9-cofilin pathway in Aβ-induced apoptosis and neurodegeneration

Protein kinase D in vascular biology and angiogenesis

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

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