High energy phosphate transfer by NDPK B/Gβγcomplexes - an alternative signaling pathway involved in the regulation of basal cAMP production

Hippe, Hans-Joerg; Wieland, Thomas

doi:10.1007/s10863-006-9035-0

Cited by 16 publications

(16 citation statements)

References 66 publications

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“…S4), indicating that both genes might be functionally relevant. G protein ␤ 1 -subunit forms a complex with NDPK B in mammalian cells (3,7,8) and the co-immunoprecipitation experiments shown in Fig. 1C indicate an identical association in zebrafish.…”

Section: Morpholino-mediated Knockdown Of the Zebrafish Ndpk A And Bmentioning

confidence: 65%

“…The two major isoforms, NDPK A and B (17-21 kDa), play crucial roles in a wide array of cellular processes [for review see (3)]. Despite their high sequence homology and the well known formation of heterohexamers to perform their house keeping enzyme activity (4), NDPK A and B have distinct cellular functions, which are based on the possibility of both isoforms contributing to multimeric protein complexes like the SET complex (5) and a complex formed with Ca 2ϩ -activated potassium channel KCa3.1 (6).…”

mentioning

confidence: 99%

“…We have previously shown that NDPK B, but not NDPK A, forms a complex with G␤␥ (7,8) and acts as a histidine kinase for G␤. The high energetic phosphate on G␤ can be specifically transferred to GDP and the GTP that is formed, induces G protein activation (3). Recent in vitro findings suggest that this phosphorelay can regulate G s protein activity independently of GPCRs in cardiomyocytes, thereby stimulating cAMP synthesis and contractility (9).…”

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confidence: 99%

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The interaction of nucleoside diphosphate kinase B with Gβγ dimers controls heterotrimeric G protein function

Hippe

Wolf

Abu-Taha

et al. 2009

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

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Heterotrimeric G proteins in physiological and pathological processes have been extensively studied so far. However, little is known about mechanisms regulating the cellular content and compartmentalization of G proteins. Here, we show that the association of nucleoside diphosphate kinase B (NDPK B) with the G protein ␤␥ dimer (G␤␥) is required for G protein function in vivo. In zebrafish embryos, morpholino-mediated knockdown of zebrafish NDPK B, but not NDPK A, results in a severe decrease in cardiac contractility. The depletion of NDPK B is associated with a drastic reduction in G␤ 1␥2 dimer expression. Moreover, the protein levels of the adenylyl cyclase (AC)-regulating G␣ s and G␣i subunits as well as the caveolae scaffold proteins caveolin-1 and -3 are strongly reduced. In addition, the knockdown of the zebrafish G␤ 1 orthologs, G␤1 and G␤1like, causes a cardiac phenotype very similar to that of NDPK B morphants. The loss of G␤ 1/G␤1like is associated with a down-regulation in caveolins, AC-regulating G␣-subunits, and most important, NDPK B. A comparison of embryonic fibroblasts from wild-type and NDPK A/B knockout mice demonstrate a similar reduction of G protein, caveolin-1 and basal cAMP content in mammalian cells that can be rescued by re-expression of human NDPK B. Thus, our results suggest a role for the interaction of NDPK B with G␤␥ dimers and caveolins in regulating membranous G protein content and maintaining normal G protein function in vivo.cAMP ͉ cardiac contractility ͉ G proteins ͉ NDPK ͉ zebrafish S ignaling through the activation of G proteins represents the most widely used signaling pathway in mammalian biology (1). A variety of G protein-coupled receptors (GPCRs) mediate extracellular signals via heterotrimeric G proteins, which are composed of a guanine nucleotide binding ␣-subunit (G␣), as well as a ␤-subunit (G␤) and a ␥-subunit (G␥). Upon GPCR activation, the bound GDP in G␣ is exchanged for GTP and both the GTP-liganded G␣ and the stable dimer G␤␥ regulate downstream effectors (2).Nucleoside diphosphate kinases (NDPKs), which catalyze the transfer of ␥-phosphate between NTPs and NDPs, represent a family of multifunctional proteins encoded by nine human nm23 genes. The two major isoforms, NDPK A and B (17-21 kDa), play crucial roles in a wide array of cellular processes [for review see (3)]. Despite their high sequence homology and the well known formation of heterohexamers to perform their house keeping enzyme activity (4), NDPK A and B have distinct cellular functions, which are based on the possibility of both isoforms contributing to multimeric protein complexes like the SET complex (5) and a complex formed with Ca 2ϩ -activated potassium channel KCa3.1 (6). In such complexes, NDPK not only supplies NTPs but also acts as protein kinase (6). We have previously shown that NDPK B, but not NDPK A, forms a complex with G␤␥ (7, 8) and acts as a histidine kinase for G␤. The high energetic phosphate on G␤ can be specifically transferred to GDP and the GTP that is formed, induces G protei...

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Section: Morpholino-mediated Knockdown Of the Zebrafish Ndpk A And Bmentioning

confidence: 65%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The interaction of nucleoside diphosphate kinase B with Gβγ dimers controls heterotrimeric G protein function

Hippe

Wolf

Abu-Taha

et al. 2009

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

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“…NDPK is capable of maintaining nucleotide levels in mammals, implying NDPK may be a critical component of G protein-mediated signaling (2)(3)(4)(5)(6). Mammalian NDPK is a multifunctional enzyme, involved in the regulation of growth and development (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Arabidopsis nucleoside diphosphate kinase-2 as a plant GTPase activating protein

Shen¹,

Han²,

Kim³

et al. 2008

BMB Reports

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Nucleoside diphosphate kinase (NDPK) is involved in multiple signaling pathways in mammalian systems, including G-protein signaling. Arabidopsis NDPK2, like its mammalian counterparts, is multifunctional despite its initial discovery phytochrome-interacting protein. This similarity raises the possibility that NDPK2 may play a role in G-protein signaling in plants. In the present study, we explore the potential relationship between NDPK2 and the small G proteins, Pra2 and Pra3, as well as the heterotrimeric G protein, GPA1. We report a physical interaction between NDPK2 and these small G proteins, and demonstrate that NDPK2 can stimulate their GTPase activities. Our results suggest that NDPK2 acts as a GTPase-activating protein for small G proteins in plants. We propose that NDPK2 might be a missing link between the phytochromemediated light signaling and G protein-mediated signaling.[BMB reports 2008; 41(9): 645-650]

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“…28,32 For a more detailed overview of these mechanisms, the reader is referred to previous reviews. [33][34][35][36] Although NDPK-C can activate G proteins similar to NDPK-B (discussed below), other potential NDPK-C phosphorylation targets have not yet been identified.…”

Section: Mechanisms Of G-protein Signaling Regulation By Ndpksmentioning

confidence: 99%

Regulation of heterotrimeric G-protein signaling by NDPK/NME proteins and caveolins: an update

Abu-Taha

Heijman

Feng

et al. 2018

Laboratory Investigation

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Heterotrimeric G proteins are pivotal mediators of cellular signal transduction in eukaryotic cells and abnormal G-protein signaling plays an important role in numerous diseases. During the last two decades it has become evident that the activation status of heterotrimeric G proteins is both highly localized and strongly regulated by a number of factors, including a receptor-independent activation pathway of heterotrimeric G proteins that does not involve the classical GDP/GTP exchange and relies on nucleoside diphosphate kinases (NDPKs). NDPKs are NTP/NDP transphosphorylases encoded by the nme/nm23 genes that are involved in a variety of cellular events such as proliferation, migration, and apoptosis. They therefore contribute, for example, to tumor metastasis, angiogenesis, retinopathy, and heart failure. Interestingly, NDPKs are translocated and/or upregulated in human heart failure. Here we describe recent advances in the current understanding of NDPK functions and how they have an impact on local regulation of G-protein signaling.

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High energy phosphate transfer by NDPK B/Gβγcomplexes - an alternative signaling pathway involved in the regulation of basal cAMP production

Cited by 16 publications

References 66 publications

The interaction of nucleoside diphosphate kinase B with Gβγ dimers controls heterotrimeric G protein function

The interaction of nucleoside diphosphate kinase B with Gβγ dimers controls heterotrimeric G protein function

Arabidopsis nucleoside diphosphate kinase-2 as a plant GTPase activating protein

Regulation of heterotrimeric G-protein signaling by NDPK/NME proteins and caveolins: an update

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