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Gartner, Anton
DNA Damage Response and Genetic Toxicology
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The NM23-H1/H2 homolog NDK-1 is required for full activation of Ras signaling in C. elegans

Author(s)
Masoudi, NedaFancsalszky, LucaPourkarimi, EhsanVellai, TiborAlexa, AnitaRemenyi, AttilaGartner, AntonMehta, AnilTakacs-Vellai, Krisztina
Issued Date
2013-08
DOI
10.1242/dev.094011
URI
https://scholarworks.unist.ac.kr/handle/201301/30985
Fulltext
https://dev.biologists.org/content/140/16/3486
Citation
DEVELOPMENT, v.140, no.16, pp.3486 - 3495
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.
Publisher
COMPANY BIOLOGISTS LTD
ISSN
0950-1991
Keyword (Author)
C. elegansKSR scaffoldsNm23/NDPKNMERas signaling
Keyword
HETEROTRIMERIC G-PROTEINDIPHOSPHATE KINASE-BKSR-1 GENE ENCODESCAENORHABDITIS-ELEGANSNM23 EXPRESSIONPHOSPHORYLATIONRECEPTORPROLIFERATIONSUPPRESSORTRANSDUCTION

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