RGS19 inhibits Ras signaling through Nm23H1/2-mediated phosphorylation of the kinase suppressor of Ras

Tso, Prudence H.; Wang, Yingchun; Yung, Lisa Y.; Tong, Yao; Lee, Maggie M. K.; Wong, Yung Hou

doi:10.1016/j.cellsig.2013.02.010

Cited by 25 publications

(35 citation statements)

References 46 publications

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“…Thus, a previously proposed link between an NDPK protein and KSR scaffolds [65,66] was confirmed in vivo [59]. However, as NDK-1 is necessary for proper MAPK activation, one can conclude that it promotes the activation of Ras/MAPK signaling.…”

Section: Awd Regulates Neurotransmission Through Its Endocytic Functionmentioning

confidence: 58%

“…Inactivation of KSR1 by NME1 occurs through phosphorylation of Ser392 of this scaffold protein [65]. Thus, KSR1 is also a target of NM23-H1's histidine kinase activity, which was demonstrated in different cell lines [65,66]. In C. elegans, a genetic interaction was observed between NDK-1/NDPK and the worm KSRs [59].…”

Section: Ndpk-related Molecular Activities In Animal Modelsmentioning

confidence: 98%

“…However, as NDK-1 is necessary for proper MAPK activation, one can conclude that it promotes the activation of Ras/MAPK signaling. In human studies, however, NDPKs were shown to attenuate Ras/ERK signaling through phosphorylation of KSR scaffolds [65,66]. Moreover, cancer invasion induced by NM23-H1 silencing was reverted by a pharmacological inhibitor of the Ras/ ERK pathway, further showing an inverse relationship between NDPK activity and Ras/ERK activation in human [67].…”

Section: Awd Regulates Neurotransmission Through Its Endocytic Functionmentioning

confidence: 99%

“…These data suggest that NDK-1 is necessary for full activation of MAPK signaling in somatic tissues of the worm. Because the scaffold proteins KSR-1/KSR-2 (kinase suppressor of Ras) are indispensable for MAPK activation [64], and because several studies on human cell lines have linked NM23's function to KSR scaffolds [65,66], ndk-1(-);ksr-1(-) and ndk-1(-)ksr-2(-) double knockouts were generated to test potential genetic interactions between ndk-1 and ksr genes. In these double mutants, ndk-1 single-mutant phenotypes were enhanced.…”

Section: Awd Regulates Neurotransmission Through Its Endocytic Functionmentioning

confidence: 99%

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Nucleoside diphosphate kinases (NDPKs) in animal development

Takács‐Vellai

Vellai

Farkas

et al. 2014

Cell. Mol. Life Sci.

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In textbooks of biochemistry, nucleoside diphosphate conversion to a triphosphate by nucleoside diphosphate 'kinases' (NDPKs, also named NME or NM23 proteins) merits a few lines of text. Yet this essential metabolic function, mediated by a multimeric phosphotransferase protein, has effects that lie beyond a simple housekeeping role. NDPKs attracted more attention when NM23-H1 was identified as the first metastasis suppressor gene. In this review, we examine these NDPK enzymes from a developmental perspective because of the tractable phenotypes found in simple animal models that point to common themes. The data suggest that NDPK enzymes control the availability of surface receptors to regulate cellsensing cues during cell migration. NDPKs regulate different forms of membrane enclosure that engulf dying cells during development. We suggest that NDPK enzymes have been essential for the regulated uptake of objects such as bacteria or micronutrients, and this evolutionarily conserved endocytic function contributes to their activity towards the regulation of metastasis.

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Section: Awd Regulates Neurotransmission Through Its Endocytic Functionmentioning

confidence: 58%

Section: Ndpk-related Molecular Activities In Animal Modelsmentioning

confidence: 98%

Section: Awd Regulates Neurotransmission Through Its Endocytic Functionmentioning

confidence: 99%

Section: Awd Regulates Neurotransmission Through Its Endocytic Functionmentioning

confidence: 99%

See 2 more Smart Citations

Nucleoside diphosphate kinases (NDPKs) in animal development

Takács‐Vellai

Vellai

Farkas

et al. 2014

Cell. Mol. Life Sci.

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“…For example, NDPK-A interacts with and inhibits Tiam1, which acts as a guanine nucleotide exchange factor (GEF) for the Rac1 GTPase, which prevents Rac/Rho activation (16). NDPK-A interacts with Lbc to inactivate RhoA or interacts with Rad to activate Rad and inhibit the Ras pathways (17)(18)(19)(20). Hence, interaction with multiple binding partners is critical for NDPK-A to execute physiologic roles in diverse biological processes (18,(21)(22)(23).…”

mentioning

confidence: 99%

The Ubiquitin E3 Ligase SCF-FBXO24 Recognizes Deacetylated Nucleoside Diphosphate Kinase A To Enhance Its Degradation

Chen

Xiong

et al. 2015

Molecular and Cellular Biology

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The Skp-Cul-F box (SCF) ubiquitin E3 ligase machinery recognizes predominantly phosphodegrons or, less commonly, an (I/L)Q molecular signature within substrates to facilitate their recruitment in mediating protein ubiquitination and degradation. Here, we examined the molecular signals that determine the turnover of the multifunctional enzyme nucleoside diphosphate kinase A (NDPK-A) that controls cell proliferation. NDPK-A protein exhibits a half-life of ϳ6 h in HeLa cells and is targeted for ubiquitylation through actions of the F-box protein FBXO24. SCF-FBXO24 polyubiquitinates NDPK-A at K85, and two NH 2 -terminal residues, L55 and K56, were identified as important molecular sites for FBXO24 interaction. Importantly, K56 acetylation impairs its interaction with FBXO24, and replacing K56 with Q56, an acetylation mimic, reduces NDPK-A FBXO24 binding capacity. The acetyltransferase GCN5 catalyzes K56 acetylation within NDPK-A, thereby stabilizing NDPK-A, whereas GCN5 depletion in cells accelerates NDPK-A degradation. Cellular expression of an NDPK-A acetylation mimic or FBXO24 silencing increases NDPK-A life span which, in turn, impairs cell migration and wound healing. We propose that lysine acetylation when presented in the appropriate context may be recognized by some F-box proteins as a unique inhibitory molecular signal for their recruitment to restrict substrate degradation.T he stability of the majority of cellular regulatory proteins is governed by a ubiquitous disposal apparatus, the ubiquitin proteasome system (1). For proteasomal degradation, the selected protein is processed through a hierarchical, highly controlled and relatively selective system involving a series of enzymatic steps. The substrate is ubiquitinated through sequential activities of a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and, finally, a ubiquitin ligase (E3). In the cullin (CUL)-RING ubiquitin ligase superfamily, the E3 complex recognizes a specific substrate by physical interactions using adaptor or receptor-like subunits linked to a scaffold base (2-5). The S-phase kinase-associated protein 1 (Skp1)-cullin 1 (CUL1)-F-box protein (SCF) protein complex is a prototypical multicomponent subfamily of CUL-RING E3 ligases that harbors a key substrate receptor component, the F-box protein, which via Skp1 binds the scaffold protein CUL1. Within the SCF complex, the F-box protein associates with the substrate through its C-terminal substrate binding domain and then binds to Skp1 via its NH 2 -terminal Fbox domain (5). Depending on the nature of the molecular sequence within the substrate-binding pocket, F-box proteins are categorized into FbxL, FbxW, and FbxO subfamilies.An important area of investigation is elucidating the molecular signals that recruit the receptor component of SCF-based E3 ligases, the F-box protein, to their targets. It is generally established that phosphorylation within relatively short motifs (phosphodegrons) are key molecular signatures that facilitate the recruitment of F-box proteins...

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Regulation of the metastasis suppressor Nm23-H1 by tumor viruses

Banerjee

Jha

Robertson

2014

Naunyn-Schmiedeberg's Arch Pharmacol

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Metastasis is the most common cause of cancer mortality. To increase the survival of patients, it is necessary to develop more effective methods for treating as well as preventing metastatic diseases. Recent advancement of knowledge in cancer metastasis provides the basis for development of targeted molecular therapeutics aimed at the tumor cell or its interaction with the host microenvironment. Metastasis suppressor genes (MSGs) are promising targets for inhibition of the metastasis process. During the past decade, functional significance of these genes, their regulatory pathways, and related downstream effector molecules have become a major focus of cancer research. Nm23-H1, first in the family of Nm23 human homologues, is a well-characterized, anti-metastatic factor linked with a large number of human malignancies. Mounting evidence to date suggests an important role for Nm23-H1 in reducing virus-induced tumor cell motility and migration. A detailed understanding of the molecular association between oncogenic viral antigens with Nm23-H1 may reveal the underlying mechanisms for tumor virus-associated malignancies. In this review, we will focus on the recent advances to our understanding of the molecular basis of oncogenic virus-induced progression of tumor metastasis by deregulation of Nm23-H1.

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RGS19 inhibits Ras signaling through Nm23H1/2-mediated phosphorylation of the kinase suppressor of Ras

Cited by 25 publications

References 46 publications

Nucleoside diphosphate kinases (NDPKs) in animal development

Nucleoside diphosphate kinases (NDPKs) in animal development

The Ubiquitin E3 Ligase SCF-FBXO24 Recognizes Deacetylated Nucleoside Diphosphate Kinase A To Enhance Its Degradation

Regulation of the metastasis suppressor Nm23-H1 by tumor viruses

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