title: NDK-1, the homolog of NM23-H1/H2 regulates cell migration and apoptotic engulfment in C. elegans.
abstract: Abnormal regulation of cell migration and altered rearrangement of cytoskeleton are characteristic of metastatic cells. The first described suppressor of metastatic processes is NM23-H1, which displays NDPK (nucleoside-diphosphate kinase) activity. To better understand the role of nm23 genes in cell migration, we investigated the function of NDK-1, the sole Caenorhabditis elegans homolog of group I NDPKs in distal tip cell (DTC) migration. Dorsal phase of DTC migration is regulated by integrin mediated signaling. We find that ndk-1 loss of function mutants show defects in this phase. Epistasis analysis using mutants of the α-integrin ina-1 and the downstream functioning motility-promoting signaling module (referred to as CED-10 pathway) placed NDK-1 downstream of CED-10/Rac. As DTC migration and engulfment of apoptotic corpses are analogous processes, both partially regulated by the CED-10 pathway, we investigated defects of apoptosis in ndk-1 mutants. Embryos and germ cells defective for NDK-1 showed an accumulation of apoptotic cell corpses. Furthermore, NDK-1::GFP is expressed in gonadal sheath cells, specialized cells for engulfment and clearence of apoptotic corpses in germ line, which indicates a role for NDK-1 in apoptotic corpse removal. In addition to the CED-10 pathway, engulfment in the worm is also mediated by the CED-1 pathway. abl-1/Abl and abi-1/Abi, which function in parallel to both CED-10/CED-1 pathways, also regulate engulfment and DTC migration. ndk-1(-);abi-1(-) double mutant embryos display an additive phenotype (e. g. enhanced number of apoptotic corpses) which suggests that ndk-1 acts in parallel to abi-1. Corpse number in ndk-1(-);ced-10(-) double mutants, however, is similar to ced-10(-) single mutants, suggesting that ndk-1 acts downstream of ced-10 during engulfment. In addition, NDK-1 shows a genetic interaction with DYN-1/dynamin, a downstream component of the CED-1 pathway. In summary, we propose that NDK-1/NDPK might represent a converging point of CED-10 and CED-1 pathways in the process of cytoskeleton rearrangement.
authors.affiliation: Department of Genetics, Eötvös Loránd University, Budapest, Hungary.
authors.forename: Luca
authors.initials: L
authors.lastname: Fancsalszky
authors.affiliation: Department of Genetics, Eötvös Loránd University, Budapest, Hungary.
authors.forename: Eszter
authors.initials: E
authors.lastname: Monostori
authors.affiliation: Department of Genetics, Eötvös Loránd University, Budapest, Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Farkas
authors.affiliation: Department of Genetics, Eötvös Loránd University, Budapest, Hungary.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Pourkarimi
authors.affiliation: Department of Genetics, Eötvös Loránd University, Budapest, Hungary.
authors.forename: Neda
authors.initials: N
authors.lastname: Masoudi
authors.affiliation: Department of Genetics, Eötvös Loránd University, Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Hargitai
authors.affiliation: Laboratory for Molecular Oncology, Division of Molecular Medicine, Rudjer Bošković Institute, Zagreb, Croatia.
authors.forename: Maja Herak
authors.initials: MH
authors.lastname: Bosnar
authors.affiliation: Laboratory for Molecular Oncology, Division of Molecular Medicine, Rudjer Bošković Institute, Zagreb, Croatia.
authors.forename: Martina
authors.initials: M
authors.lastname: Deželjin
authors.affiliation: Department of Biological Anthropology, Eötvös Loránd University, Budapest, Hungary.
authors.forename: Annamária
authors.initials: A
authors.lastname: Zsákai
authors.affiliation: Department of Genetics, Eötvös Loránd University, Budapest, Hungary.
authors.forename: Tibor
authors.initials: T
authors.lastname: Vellai
authors.affiliation: Medical Research Institute, Ninewells Hospital Medical School, University of Dundee, Dundee, United Kingdom.
authors.forename: Anil
authors.initials: A
authors.lastname: Mehta
authors.affiliation: Department of Genetics, Eötvös Loránd University, Budapest, Hungary.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Takács-Vellai
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000235:genetics*; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism; D005804:Genes, Lethal; D006801:Humans; D009154:Mutation; D054778:NM23 Nucleoside Diphosphate Kinases / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C407268:CED-10 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D003598:Cytoskeletal Proteins; D054778:NM23 Nucleoside Diphosphate Kinases; D011993:Recombinant Fusion Proteins; C539886:abi-1 protein, C elegans; D020744:rac GTP-Binding Proteins