Modulation of cytoskeletal dynamics by mammalian nucleoside diphosphate kinase (NDPK) proteins

Abstract

Nucleoside diphosphate kinase (NDPK) proteins comprise a family of ten human isoforms that participate in the regulation of multiple cellular processes via enzymatic and non-enzymatic functions. The major enzymatic function of NDPKs is the generation of nucleoside triphosphates, such as GTP. Mechanisms behind the non-enzymatic NDPK functions are not clear, but likely involve context-dependent signaling roles of NDPK within multi-protein complexes. This is most evident for NDPK-A, which is encoded by the human NME1 gene, the first tumor metastasis suppressor gene to be identified. Understanding which protein interactions are most relevant for the biological and metastasis-related functions of NDPK will be important in the potential utilization of NDPK as a disease target. Accumulating evidence suggests that NDPK interacts with and affects various components and regulators of the cytoskeleton, including actin-binding proteins, intermediate filaments, and cytoskeletal attachment structures (adherens junctions, desmosomes and focal adhesions). We review the existing literature on this topic and highlight outstanding questions and potential future directions that should clarify the impact of NDPK on the different cytoskeletal systems.

Identification of a gene expression signature associated with the metastasis suppressor function of NME1: prognostic value in human melanoma

“…We recently showed that concomitant ablation of the NME1 and NME2 genes greatly enhances metastatic potential in a mouse model of ultraviolet light-induced melanoma ( 12 ), providing strong in vivo evidence of its metastasis suppressor function. Multiple reports suggest the NME1 protein regulates tumor cell motility via physical and functional interactions with a variety of signaling pathways ( 13 ). However, NME1 has also been reported to control RNA expression profiles in breast carcinoma ( 14 ) and melanoma cell lines ( 15 ), suggesting this activity could also mediate its metastasis suppressor function.…”

“…A role for NDPK activity in the metastasis suppressor function of NME1 has yet to be firmly established, however, with at least one study suggesting it does not contribute ( 19 ). Nonetheless, relevance of NDPK is strongly suggested in other settings by the direct association of NME1/NDPK protein with a variety of cytoskeletal and membrane mediators of cell motility ( 13 ). In addition, NDPK activity has been shown to supply GTP to dynamin during membrane remodeling and endocytosis of cell surface receptors ( 20 ), a function which could well impact metastatic potential of cancer cells.…”

Mediation of FoxO1 in Activated Neuroglia Deficient for Nucleoside Diphosphate Kinase B during Vascular Degeneration

“…It is, besides NDPK-A, the second of the two major isoforms of the NDPK family [16]. NDPK-B has been reported to play multiple roles in cellular functions, including cell proliferation, migration, apoptosis [17][18][19], and signal transduction [20][21][22]. NDPK-B also plays a role in retinopathies [23,24].…”

Plant nucleoside diphosphate kinase 1: A housekeeping enzyme with moonlighting activity

“…In animal cells, NDPKs are also recognized to play additional roles in an array of unrelated processes including transcriptional regulation of gene expression, 1 tumor metastasis, 2 signalling, 3 development, 4 mitophagy, 5 and DNA repair. 6 This functional versatility may be mediated by various moonlighting activities, including histidine protein kinase activity, 7 nuclease activity, 8,9 or their ability to interact with numerous protein partners, 10,11 DNA, 1,6 or lipid bilayer. 12,13 In plants, the NDPK family is divided into four types (I-IV) based on phylogenetic analyses and patterns of subcellular localization.…”