Nucleophosmin1 Is a Negative Regulator of the Small GTPase Rac1

Zoughlami, Younes; Stalborgh, Anne M. van; Hennik, Paula B. van; Hordijk, Peter L.

doi:10.1371/journal.pone.0068477

Cited by 9 publications

(9 citation statements)

References 49 publications

(64 reference statements)

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“…Our data provide evidence for both mechanisms. LC-MS/MS identified B23 as a Rac1 nuclear interactor, and the biochemical data attest to the physiological relevance of this interaction because B23 binds most strongly to the N-terminal region of Rac1, and not exclusively through the polybasic C-terminal region, as proposed (Zoughlami et al, 2013). This finding thus excludes the trivial explanation of a purely electrostatic interaction ( Figure 2).…”

Section: Discussionmentioning

confidence: 51%

Rac1 Nucleocytoplasmic Shuttling Drives Nuclear Shape Changes and Tumor Invasion

et al. 2015

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Nuclear membrane microdomains are proposed to act as platforms for regulation of nuclear function, but little is known about the mechanisms controlling their formation. Organization of the plasma membrane is regulated by actin polymerization, and the existence of an actin pool in the nucleus suggests that a similar mechanism might operate here. We show that nuclear membrane organization and morphology are regulated by the nuclear level of active Rac1 through actin polymerization-dependent mechanisms. Rac1 nuclear export is mediated by two internal nuclear export signals and through its interaction with nucleophosmin-1 (B23), which acts as a Rac1 chaperone inside the nucleus. Rac1 nuclear accumulation alters the balance between cytosolic Rac1 and Rho, increasing RhoA signaling in the cytoplasm and promoting a highly invasive phenotype. Nuclear Rac1 shuttling is a finely tuned mechanism for controlling nuclear shape and organization and cell invasiveness.

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Section: Discussionmentioning

confidence: 51%

Rac1 Nucleocytoplasmic Shuttling Drives Nuclear Shape Changes and Tumor Invasion

et al. 2015

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“…On one hand, active Rac1 directly interacts with STAT3 and regulates its activity by promoting its phosphorylation (Simon et al, 2000). On the other hand, Rac1 interaction with nucleophosmin-1 attenuates Rac1 signaling and inhibits cell spreading (Zoughlami et al, 2013). Moreover, increased Rac1 shuttling into the nucleus accelerates cell division (Michaelson et al, 2008).…”

Section: Rho Gtpase Signaling From Nucleusmentioning

confidence: 99%

Multifaceted Rho GTPase Signaling at the Endomembranes

Phuyal

Farhan

2019

Front. Cell Dev. Biol.

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The Rho family of small GTPases orchestrates fundamental biological processes such as cell cycle progression, cell migration, and actin cytoskeleton dynamics, and their aberrant signaling is linked to numerous human diseases and disorders. Traditionally, active Rho GTPase proteins were proposed to reside and function predominantly at the plasma membrane. While this view still holds true, it is emerging that active pool of multiple Rho GTPases are in part localized to endomembranes such as endosomes and the Golgi. In this review, we will focus on the intracellular pools and discuss how their local activation contributes to the shaping of various cellular processes. Our main focus will be on Rho signaling from the endosomes, Golgi, mitochondria and nucleus and how they regulate multiple cellular events such as receptor trafficking, cell proliferation and differentiation, cell migration and polarity.

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“…Another possibility is that NPM is phosphorylated at T199 in the nucleus and, thereafter, translocates from the nucleus to the cytoplasm. Of note, it has been reported that activated small GTPase Rac1, a protein that is highly relevant to HUVECs (59), may favor translocation of phosphorylated NPM from the nucleus to the cytoplasm (60). In our experimental conditions, the kinase that phosphorylates NPM at T199 and the cellular location of this phosphorylation, whether in the cytoplasm or in the nucleus, remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress disassembles the p38/NPM/PP2A complex, which leads to modulation of nucleophosmin‐mediated signaling to DNA damage response

et al. 2016

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Oxidative stress is a leading cause of endothelial dysfunction. The p38 MAPK pathway plays a determinant role in allowing cells to cope with oxidative stress and is tightly regulated by a balanced interaction between p38 protein and its interacting partners. By using a proteomic approach, we identified nucleophosmin (NPM) as a new partner of p38 in HUVECs. Coimmunoprecipitation and microscopic analyses confirmed the existence of a cytosolic nucleophosmin (NPM)/p38 interaction in basal condition. Oxidative stress, which was generated by exposure to 500 µM H2O2, induces a rapid dephosphorylation of NPM at T199 that depends on phosphatase PP2A, another partner of the NPM/p38 complex. Blocking PP2A activity leads to accumulation of NPM-pT199 and to an increased association of NPM with p38. Concomitantly to its dephosphorylation, oxidative stress promotes translocation of NPM to the nucleus to affect the DNA damage response. Dephosphorylated NPM impairs the signaling of oxidative stress-induced DNA damage via inhibition of the phosphorylation of ataxia-telangiectasia mutated and DNA-dependent protein kinase catalytic subunit. Overall, these results suggest that the p38/NPM/PP2A complex acts as a dynamic sensor, allowing endothelial cells to react rapidly to acute oxidative stress.-Guillonneau, M., Paris, F., Dutoit, S., Estephan, H., Bénéteau, E., Huot, J., Corre, I. Oxidative stress disassembles the p38/NPM/PP2A complex, which leads to modulation of nucleophosmin-mediated signaling to DNA damage response.

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Nucleophosmin1 Is a Negative Regulator of the Small GTPase Rac1

Cited by 9 publications

References 49 publications

Rac1 Nucleocytoplasmic Shuttling Drives Nuclear Shape Changes and Tumor Invasion

Rac1 Nucleocytoplasmic Shuttling Drives Nuclear Shape Changes and Tumor Invasion

Multifaceted Rho GTPase Signaling at the Endomembranes

Oxidative stress disassembles the p38/NPM/PP2A complex, which leads to modulation of nucleophosmin‐mediated signaling to DNA damage response

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