The metastasis suppressor protein Nme1 is a concentration dependent modulator of the Ca2+/calmodulin-dependent protein kinase II

Nucleoside diphosphate kinases(Nmes or NDPKs) have been implicated in a multitude of cellular processes, including an important role in metastasis suppression, and several enzymatic activities have been assigned to the Nme family. Nevertheless, for many of these processes, it has not been possible to establish a strong connection between Nme enzymatic activity and the relevant biological function. We hypothesized that, in addition to its known enzymatic functions, members of the Nme family might also regulate signaling cascadesby acting on key signal transducers. Accordingly, here we show that Nme1 directly interacts with the calcium/calmodulin-dependent kinase II (CaMKII). Using purified proteins, we monitored the phosphorylation of a number of CaMKII substrates and determined that at nanomolar levels Nme1 enhances the phosphorylation of T-type substrates; this modulation shifts to inhibition at low micromolar concentrations. Specifically, the autophosphorylationof CaMKII at Thr286 is completely inhib...