The Metastasis Suppressor Candidate Nucleotide Diphosphate Kinase NM23 Specifically Interacts with Members of the ROR/RZR Nuclear Orphan Receptor Subfamily

Paravicini, Gerhard; Steinmayr, Markus; André, Emmanuel; Becker‐André, Michael

doi:10.1006/bbrc.1996.1471

Cited by 38 publications

(23 citation statements)

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“…Members of the ROR͞RZR nuclear orphan receptor subfamily are reported to interact with nm23 in vitro and regulate the transcription of genes, including N-myc (42). Moreover, an isoform of mouse nm23, nm23 M1, forms molecular complexes with ␤-tubulin in myogenic cells during the process of differentiation, although its biological significance is not well known (43).…”

Section: Nm23h1mentioning

confidence: 99%

Tumor metastasis suppressor nm23H1 regulates Rac1 GTPase by interaction with Tiam1

Otsuki

Tanaka

Yoshii

et al. 2001

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

180

138

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The putative tumor metastasis suppressor nm23H1 was originally identified in murine melanomas by subtraction cloning. It displays nucleoside diphosphate kinase activity and regulates cellular events, including growth and development. Recently nm23H1 has been reported to also act as a GTPase-activating protein of the Ras-related GTPase Rad. We attempted to determine whether nm23H1 also regulates Rho-family GTPases. Although we were unable to detect a direct association between nm23H1 and Rhofamily GTPases, nm23H1 was shown to be associated with a Rac1-specific nucleotide exchange factor, Tiam1, by interaction with its amino-terminal region in extracts from the cells expressing exogenous Tiam1 and from native tissue. Overexpression of nm23H1 inhibited the Tiam1-induced production of GTP-bound Rac1 and activation of c-Jun kinase. On the other hand, forced overexpression of the wild type, but not the kinase-inactivated mutant of nm23H1, converted the GDP-bound forms of Rac1, Cdc42, and RhoA to their GTP-bound forms in vitro by its nucleoside diphosphate kinase activity, but nm23H1 alone apparently did not produce the GTP-bound form of these GTPases in vivo. These results suggest that nm23H1 negatively regulates Tiam1 and inhibits Rac1 activation in vivo. Moreover, adhesion-stimulated membrane ruffles of Rat1 fibroblasts were reduced by overexpression of nm23H1. Based on these observations, we concluded that we had identified a function of nm23H1 as a regulator of Rac1 and that it may be related to the effect of nm23H1 as a tumor metastasis suppressor.

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Section: Nm23h1mentioning

confidence: 99%

Tumor metastasis suppressor nm23H1 regulates Rac1 GTPase by interaction with Tiam1

Otsuki

Tanaka

Yoshii

et al. 2001

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

180

138

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“…However, the mechanism of regulation of these signaling pathways by NM23 family proteins is unknown. To date, NM23 family proteins have been shown to associate with several cellular proteins, including glyceraldehyde-3-phosphate dehydrogenase (9), Hsc70 (70-kDa heat shock cognate protein) (10), telomere (11), ROR␣ (retinoid acid receptor-related orphan receptor ␣)/RZR␤ (retinoid Z receptor ␤) (12), Rad, a Ras-related small GTPase (13), creatine kinase and antioxidant protein (14), and thromboxane A2 receptor, a G protein-coupled receptor (6). These results suggest that the identification of additional binding partners of NM23 proteins will provide greater insight into the regulation and biological function of NM23 family proteins.…”

mentioning

confidence: 99%

NM23-H1 Tumor Suppressor Physically Interacts with Serine-Threonine Kinase Receptor-associated Protein, a Transforming Growth Factor-β (TGF-β) Receptor-interacting Protein, and Negatively Regulates TGF-β Signaling

Seong

Jung

2007

Journal of Biological Chemistry

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NM23-H1 is a member of the NM23/NDP kinase gene family and a putative metastasis suppressor. Previously, a screen for NM23-H1-interacting proteins that could potentially modulate its activity identified serine-threonine kinase receptor-associated protein (STRAP), a transforming growth factor (TGF) . Ectopic expression of wild-type NM23-H1, but not NM23-H1(C145S), negatively regulated TGF-␤ signaling in a dose-dependent manner, enhanced stable association between the TGF-␤ receptor and Smad7, and prevented nuclear translocation of Smad3. Similarly, wild-type NM23-H1 inhibited TGF-␤-induced apoptosis and growth inhibition, whereas NM23-H1(C145S) had no effect. Knockdown of NM23-H1 by small interfering RNA stimulated TGF-␤ signaling. Coexpression of wild-type STRAP, but not STRAP(C152S/C270S), significantly stimulated NM23-H1-induced growth of HaCaT cells. These results suggest that the direct interaction of NM23-H1 and STRAP is important for the regulation of TGF-␤-dependent biological activity as well as NM23-H1 activity.-The NM23 family of genes is characterized by reduced expression in certain highly metastatic cell lines and tumors (1).In humans, the eight NM23 genes that have been identified to date, NM23-H1, , and NM23-H8, encode NDP kinases or homologous isoforms (2). However, although NM23-H1 was initially identified as a putative metastasis suppressor, its enzymatic activity does not appear to be responsible for its function as a metastasis suppressor during tumor progression (3). Studies of NM23 family proteins in other species have provided evidence for their role in proliferation, differentiation, apoptosis, development, and endocytosis (4). In Drosophila, for example, abnormal wing discs (awd) is an NDP kinase, and the killerof-prune mutation of awd (awd k-pn ) causes abnormalities in cell morphology and differentiation (5). Recently, both NM23-H1 and NM23-H2 have been reported to play a role in endocytosis (6). In addition, NM23 has been associated with the differentiation of human MDA-MB-435 breast carcinoma cells (7). The ability of NM23 family proteins to regulate such a diverse set of cellular processes has recently been linked to their ability to modulate signal transduction by a diverse set of growth factors, such as transforming growth factor-␤1 (TGF-␤1), 2 nerve growth factor, platelet-derived growth factor, and insulin-like growth factor-1 (8). However, the mechanism of regulation of these signaling pathways by NM23 family proteins is unknown. To date, NM23 family proteins have been shown to associate with several cellular proteins, including glyceraldehyde-3-phosphate dehydrogenase (9), Hsc70 (70-kDa heat shock cognate protein) (10), telomere (11), ROR␣ (retinoid acid receptor-related orphan receptor ␣)/RZR␤ (retinoid Z receptor ␤) (12), Rad, a Ras-related small GTPase (13), creatine kinase and antioxidant protein (14), and thromboxane A2 receptor, a G protein-coupled receptor (6). These results suggest that the identification of additional binding partners of NM23 proteins will provide gre...

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“…The biochemical mechanism of metastasis suppression is thought to involve attenuation of signaling for tumor cell motility, invasion, and colonization. At least four classes of Nm23 biochemical activities may contribute to altered signaling, including proteinprotein interactions (4,12,16,28,44,47,51,55,57,58,66), regulation of GTP-binding protein function (15,48,50,72,79,82), DNA-associated activities (14,53,54,63), and histidinedependent protein phosphotransferase activity (11,73,74). A role for KSR1 in Nm23-H1 attenuation of Erk activation was investigated.…”

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confidence: 99%

Nm23-H1 Metastasis Suppressor Expression Level Influences the Binding Properties, Stability, and Function of the Kinase Suppressor of Ras1 (KSR1) Erk Scaffold in Breast Carcinoma Cells

Salerno

Palmieri

Bouadis

et al. 2005

Molecular and Cellular Biology

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Metastatic disease is a significant contributor to cancer patient mortality. We previously reported that the Kinase Suppressor of Ras1 (KSR1) scaffold protein for the Erk mitogen-activated protein kinase pathway coimmunoprecipitated the metastasis suppressor protein Nm23-H1. We now hypothesize that altered expression levels of Nm23-H1 influence the binding properties, stability, and function of the KSR1 scaffold. Increased coimmunoprecipitation of Hsp90 with KSR1 was observed in either stable or transient transfectants of nm23-H1 in MDA-MB-435 human breast carcinoma cells. Similar trends were also observed in the cytoplasmic and nuclear fractions of cells. Cells expressing high levels of Nm23-H1 exhibited increased KSR1 degradation in the presence of either cycloheximide or an Hsp90-directed drug currently in clinical trial, 17-allylamino-17-demethoxygeldanamycin (17-AAG). In agreement with KSR1 degradation data, high-Nm23-H1-expression cells were preferentially inhibited in anchorage-independent colonization assays by 17-AAG. KSR1 scaffold binding patterns are dynamic in both the cytoplasmic and nuclear compartments, modulated by metastasis suppressor expression. Metastasis suppressor expression levels can impact traditional signaling pathways, such as the Erk pathway, resulting in altered tumor cell sensitivity to cancer therapeutics.

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The Metastasis Suppressor Candidate Nucleotide Diphosphate Kinase NM23 Specifically Interacts with Members of the ROR/RZR Nuclear Orphan Receptor Subfamily

Cited by 38 publications

References 0 publications

Tumor metastasis suppressor nm23H1 regulates Rac1 GTPase by interaction with Tiam1

Tumor metastasis suppressor nm23H1 regulates Rac1 GTPase by interaction with Tiam1

NM23-H1 Tumor Suppressor Physically Interacts with Serine-Threonine Kinase Receptor-associated Protein, a Transforming Growth Factor-β (TGF-β) Receptor-interacting Protein, and Negatively Regulates TGF-β Signaling

Nm23-H1 Metastasis Suppressor Expression Level Influences the Binding Properties, Stability, and Function of the Kinase Suppressor of Ras1 (KSR1) Erk Scaffold in Breast Carcinoma Cells

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