Casein kinase 2-dependent serine phosphorylation of MuSK regulates acetylcholine receptor aggregation at the neuromuscular junction.
The release of Agrin by motoneurons activates the muscle-specific receptor tyrosine kinase (MuSK) as the main organizer of subsynaptic specializations at the neuromuscular junction. MuSK downstream signaling is largely undefined. Here we show that protein kinase CK2 interacts and colocalizes with MuSK at post-synaptic specializations. We observed CK2-mediated phosphorylation of serine residues within the kinase insert (KI) of MuSK. Inhibition or knockdown of CK2, or exchange of phosphorylatable serines by alanines within the KI of MuSK, impaired acetylcholine receptor (AChR) clustering, whereas their substitution by residues that imitate constitutive phosphorylation led to aggregation of AChRs even in the presence of CK2 inhibitors. Impairment of AChR cluster formation after replacement of MuSK KI with KIs of other receptor tyrosine kinases correlates with potential CK2-dependent serine phosphorylation within KIs. MuSK activity was unchanged but AChR stability decreased in the presence of CK2 inhibitors. Muscle-specific CK2beta knockout mice develop a myasthenic phenotype due to impaired muscle endplate structure and function. This is the first description of a regulatory cross-talk between MuSK and CK2 and of a role for the KI of the receptor tyrosine kinase MuSK for the development of subsynaptic specializations.
Cheusova
Tatiana
T
Institut für Biochemie, Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany.
Khan
Muhammad Amir
MA
Schubert
Steffen Wolfgang
SW
Gavin
Anne-Claude
AC
Buchou
Thierry
T
Jacob
Germaine
G
Sticht
Heinrich
H
Allende
Jorge
J
Boldyreff
Brigitte
B
Brenner
Hans Rudolf
HR
Hashemolhosseini
Said
S
D000595:Amino Acid Sequence; D000818:Animals; D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D009469:Neuromuscular Junction / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D011950:Receptors, Cholinergic; D012694:Serine; C511695:MuSK protein, mouse; C475048:MuSK protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D047390:Casein Kinase II