This work defines the potential roles of nucleoside diphosphate kinase A (NM23) and lipid signal molecules in metastasis regulation. This is significant to understand the mechanism of NM23-H1 metastasis suppression and to discover novel pathways for clinical stimulation of metastasis suppression. The decrease of NM23-H1 concentration with metastasis has been documented in many cancers. We believe NM23-H1 regulates metastasis through lipid signal modulation, and will show the interaction of NM23-H1 with the lysophosphatidic acid receptor 1 (EDG2) and two lipid messengers, lysophosphatidic acid (LPA) and lysophosphatidylcholine (LPC). NM23-H1 is a known histidine and aspartic acid kinase, and we used our novel detection method to quantitate the H/D phosphorylations gained and lost on the interaction partners of NM23-H1, focusing on the Ras oncogene network (RON) proteins and EDG2. We have observed the decrease of NM23-H1 throughout cancer progression and an inverse relationship between NM23-H1 and EDG2. EGD2 is important in lipid signaling, and the connection between lipid signaling and metastasis has not been fully explored. Our central hypothesis is that NM23-H1 serves as a go/no go switch for metastasis, using phosphorylations to modulate both the RON proteins and the lipid signal concentrations through the EDG2 receptor, thereby mediating cellular responses. Phosphorylation-based regulatory processes could have evolved from ancient bacterial regulatory mechanisms, adapted to the needs of eukaryotic cells. NM23-H1 regulation through lipid signaling could represent the first characterized human two-component regulation system.

Lipid signaling through NM23-H1 as a possible suppressor of metastasis

249th National Meeting (2015)

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