Protein kinase CK2 acts as a signal molecule switching between the NDPK-A/AMPK alpha1 complex and NDPK-B.
Previously we elucidated the molecular interaction between the nucleoside diphosphate kinase A (NDPK-A)/AMP-activated protein kinase (AMPK) alpha1 complex, discovering a process we termed "substrate channeling." Here, we investigate the protein-protein interaction of the substrate channeling complex with the pleiotropic protein kinase, CK2 (formerly casein kinase 2). We show that CK2 is part of the NDPK-A/AMPK alpha1 complex under basal (background AMPK activity) conditions, binding directly to each of the complex components independently. We report that when S122 on NDPK-A is phosphorylated by AMPK alpha1 in vivo, (i.e., stimulation of AMPK using either metformin or phenformin) initiating the substrate channeling mechanism, the catalytic subunit of CK2 (CK2alpha) is expelled from the complex and translocates to bind NDPK-B, a closely related but independent isoform of NDPK. Thus, we find that the AMPK-dependent phospho-status of S122 on NDPK-A determines whether CK2alpha swaps partners between NDPK-A and NDPK-B. This is the first reported linkage between NDPK-A and NDPK-B via a phosphorylation pathway and could explain the complex biology of NDPK. This study also offers an explanation as to how CK2alpha exclusion mutations (S120A or S122D of NDPK-A) on NDPK-A might have implications in cancer biology and general cellular energy metabolism.
Crawford
Russell M
RM
Division of Maternal and Child Health Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
Treharne
Kate J
KJ
Arnaud-Dabernat
Sandrine
S
Daniel
Jean-Yves
JY
Foretz
Marc
M
Viollet
Benoit
B
Mehta
Anil
A
D055372:AMP-Activated Protein Kinases; D000595:Amino Acid Sequence; D047390:Casein Kinase II / Q000737:chemistry / Q000378:metabolism*; D020134:Catalytic Domain; D006801:Humans; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism*; D054778:NM23 Nucleoside Diphosphate Kinases; D009701:Nucleoside-Diphosphate Kinase / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport; D015398:Signal Transduction
D009097:Multienzyme Complexes; D054778:NM23 Nucleoside Diphosphate Kinases; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human; D009701:Nucleoside-Diphosphate Kinase