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The NM23-H1/H2 homolog NDK-1 is required for full activation of Ras signaling in C. elegans
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 re...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Company of Biologists
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3737725/ https://www.ncbi.nlm.nih.gov/pubmed/23900546 http://dx.doi.org/10.1242/dev.094011 |
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author | Masoudi, Neda Fancsalszky, Luca Pourkarimi, Ehsan Vellai, Tibor Alexa, Anita Reményi, Attila Gartner, Anton Mehta, Anil Takács-Vellai, Krisztina |
author_facet | Masoudi, Neda Fancsalszky, Luca Pourkarimi, Ehsan Vellai, Tibor Alexa, Anita Reményi, Attila Gartner, Anton Mehta, Anil Takács-Vellai, Krisztina |
author_sort | Masoudi, Neda |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3737725 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Company of Biologists |
record_format | MEDLINE/PubMed |
spelling | pubmed-37377252013-08-21 The NM23-H1/H2 homolog NDK-1 is required for full activation of Ras signaling in C. elegans Masoudi, Neda Fancsalszky, Luca Pourkarimi, Ehsan Vellai, Tibor Alexa, Anita Reményi, Attila Gartner, Anton Mehta, Anil Takács-Vellai, Krisztina Development Research Articles 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. Company of Biologists 2013-08-15 /pmc/articles/PMC3737725/ /pubmed/23900546 http://dx.doi.org/10.1242/dev.094011 Text en © 2013. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by-nc-sa/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
spellingShingle | Research Articles Masoudi, Neda Fancsalszky, Luca Pourkarimi, Ehsan Vellai, Tibor Alexa, Anita Reményi, Attila Gartner, Anton Mehta, Anil Takács-Vellai, Krisztina The NM23-H1/H2 homolog NDK-1 is required for full activation of Ras signaling in C. elegans |
title | The NM23-H1/H2 homolog NDK-1 is required for full activation of Ras signaling in C. elegans |
title_full | The NM23-H1/H2 homolog NDK-1 is required for full activation of Ras signaling in C. elegans |
title_fullStr | The NM23-H1/H2 homolog NDK-1 is required for full activation of Ras signaling in C. elegans |
title_full_unstemmed | The NM23-H1/H2 homolog NDK-1 is required for full activation of Ras signaling in C. elegans |
title_short | The NM23-H1/H2 homolog NDK-1 is required for full activation of Ras signaling in C. elegans |
title_sort | nm23-h1/h2 homolog ndk-1 is required for full activation of ras signaling in c. elegans |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3737725/ https://www.ncbi.nlm.nih.gov/pubmed/23900546 http://dx.doi.org/10.1242/dev.094011 |
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