title: The NM23-H1/H2 homolog NDK-1 is required for full activation of Ras signaling in C. elegans.
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.
authors.affiliation: Department of Genetics, Eötvös Loránd University, Pázmány Péter stny. 1/C, H-1117 Budapest, Hungary.
authors.forename: Neda
authors.initials: N
authors.lastname: Masoudi
authors.forename: Luca
authors.initials: L
authors.lastname: Fancsalszky
authors.forename: Ehsan
authors.initials: E
authors.lastname: Pourkarimi
authors.forename: Tibor
authors.initials: T
authors.lastname: Vellai
authors.forename: Anita
authors.initials: A
authors.lastname: Alexa
authors.forename: Attila
authors.initials: A
authors.lastname: Reményi
authors.forename: Anton
authors.initials: A
authors.lastname: Gartner
authors.forename: Anil
authors.initials: A
authors.lastname: Mehta
authors.forename: Krisztina
authors.initials: K
authors.lastname: Takács-Vellai
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000196:embryology / Q000201:enzymology* / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D047108:Embryonic Development; D004789:Enzyme Activation; D004843:Epistasis, Genetic; D005260:Female; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D011905:Genes, ras; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D054778:NM23 Nucleoside Diphosphate Kinases / Q000235:genetics / Q000378:metabolism*; D019683:Penetrance; D025941:Protein Interaction Mapping; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D014844:Vulva / Q000201:enzymology / Q000254:growth & development / Q000473:pathology; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D054778:NM23 Nucleoside Diphosphate Kinases; C460981:ksr-2 protein, C elegans; D011494:Protein Kinases; C097199:KSR-1 protein kinase; C454817:lin-45 protein, C elegans; D048490:raf Kinases; D019950:Mitogen-Activated Protein Kinase 1; C085697:mpk-1 protein, C elegans
keywords: C. elegans; KSR scaffolds; NME; Nm23/NDPK; Ras signaling
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