The Metastasis Suppressor Protein Nme1 Is a Concentration-Dependent Modulator of Ca 2+ /Calmodulin-Dependent Protein Kinase II
Biochemistry. 2019-05-29; 58(24): 2710-2714
DOI: 10.1021/acs.biochem.9b00121
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Royer L(1), Shangraw K(1), Herzog JJ(1), Pouvreau S(2)(3), Marr MT 2nd(1)(4),
Paradis S(1)(5).
Author information:
(1)Department of Biology , Brandeis University , Waltham , Massachusetts 02454 ,
United States.
(2)Interdisciplinary Institute for Neuroscience , CNRS, UMR5297 , F-33000
Bordeaux , France.
(3)University of Bordeaux , Interdisciplinary Institute for Neuroscience,
UMR5297 , F-33000 Bordeaux , France.
(4)Rosenstiel Basic Medical Sciences Research Center , Brandeis University ,
Waltham , Massachusetts 02453 , United States.
(5)Volen Center for Complex Systems , Brandeis University , Waltham ,
Massachusetts 02454 , United States.
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 cascades by
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 autophosphorylation of CaMKII
at Thr286 is completely inhibited by 2 μM Nme1, a feature that distinguishes
Nme1 from other known endogenous CaMKII inhibitors. Importantly, CaMKII
inhibition does not require phosphotransfer activity by Nme1 because the
kinase-dead Nme1 H118F mutant is as effective as the wild-type form of the
enzyme. Our results provide a novel molecular mechanism whereby Nme1 could
modulate diverse cellular processes in a manner that is independent of its known
enzymatic activities.
DOI: 10.1021/acs.biochem.9b00121
PMCID: PMC6768392
PMID: 31141673 [Indexed for MEDLINE]