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The NM23-H1/H2 homolog NDK-1 is required for full activation of Ras signaling in C. elegans

Masoudi, Neda and Fancsalszky, Luca and Pourkarimi, Ehsan and Vellai, Tibor and Alexa, Anita and Reményi, Attila and Gartner, Anton and Mehta, Anil and Vellainé Takács, Krisztina (2013) The NM23-H1/H2 homolog NDK-1 is required for full activation of Ras signaling in C. elegans. DEVELOPMENT, 140 (16). pp. 3486-3495. ISSN 0950-1991

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Abstract

The group I members of the Nm23 (non-metastatic) gene family encode nucleoside diphosphate kinases (NDPKs) that have been implicated in the regulation of cell migration, proliferation and differentiation. Despite their developmental and medical significance, the molecular functions of these NDPKs remain ill defined. To minimize confounding effects of functional compensation between closely related Nm23 family members, we studied ndk-1, the sole Caenorhabditis elegans ortholog of group I NDPKs, and focused on its role in Ras/mitogen-activated protein kinase (MAPK)-mediated signaling events during development. ndk-1 inactivation leads to a protruding vulva phenotype and affects vulval cell fate specification through the Ras/MAPK cascade. ndk-1 mutant worms show severe reduction of activated, diphosphorylated MAPK in somatic tissues, indicative of compromised Ras/MAPK signaling. A genetic epistasis analysis using the vulval induction system revealed that NDK-1 acts downstream of LIN-45/Raf, but upstream of MPK-1/MAPK, at the level of the kinase suppressors of ras (KSR-1/2). KSR proteins act as scaffolds facilitating Ras signaling events by tethering signaling components, and we suggest that NDK-1 modulates KSR activity through direct physical interaction. Our study reveals that C. elegans NDK-1/Nm23 influences differentiation by enhancing the level of Ras/MAPK signaling. These results might help to better understand how dysregulated Nm23 in humans contributes to tumorigenesis. © 2013. Published by The Company of Biologists Ltd.

Item Type: Article
Uncontrolled Keywords: Western blotting; vulva; SIGNAL TRANSDUCTION; protein degradation; priority journal; PHENOTYPE; nonhuman; Genotype; gene sequence; Female; Epistasis; enzyme activity; enzyme activation; cell migration; cell fate; Cell Differentiation; Caenorhabditis elegans; ARTICLE; unclassified drug; Ras protein; nucleoside diphosphate kinase NM23; nucleoside diphosphate kinase 1; nucleoside diphosphate kinase; mitogen activated protein kinase; Ras signaling; NME; Nm23/NDPK; KSR scaffolds; C. ELEGANS
Subjects: Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3011 Biochemistry / biokémia
Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3015 Molecular biology / molekuláris biológia
SWORD Depositor: MTMT SWORD
Depositing User: MTMT SWORD
Date Deposited: 13 May 2014 07:53
Last Modified: 14 May 2014 07:16
URI: http://real.mtak.hu/id/eprint/12737

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