Casein kinase 2-dependent serine phosphorylation of MuSK regulates acetylcholine receptor aggregation at the neuromuscular junction

@article{citeulike:744624, abstract = {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 CK2[beta] 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. 10.1101/gad.375206}, author = {Cheusova, Tatiana and Khan, Muhammad A. and Schubert, Steffen W. and Gavin, Anne-Claude and Buchou, Thierry and Jacob, Germaine and Sticht, Heinrich and Allende, Jorge and Boldyreff, Brigitte and Brenner, Hans R. and Hashemolhosseini, Said }, citeulike-article-id = {744624}, comment = {CK2beta-MuSK interaction responsible for AChR clustering in NMJ RNAi CK2beta kills cells, not CK2alpha !}, doi = {10.1101/gad.375206}, journal = {Genes Dev.}, keywords = {ck2, nmj, phosphorylation}, month = {July}, number = {13}, pages = {1800--1816}, posted-at = {2008-04-21 15:03:46}, priority = {0}, title = {Casein kinase 2-dependent serine phosphorylation of MuSK regulates acetylcholine receptor aggregation at the neuromuscular junction}, url = {http://dx.doi.org/10.1101/gad.375206}, volume = {20}, year = {2006} }

TY - JOUR ID - citeulike:744624 L3 - citeulike-article-id:744624 TI - Casein kinase 2-dependent serine phosphorylation of MuSK regulates acetylcholine receptor aggregation at the neuromuscular junction JF - Genes Dev. VL - 20 IS - 13 SP - 1800 EP - 1816 N2 - 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 CK2[beta] 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. 10.1101/gad.375206 KW - ck2 KW - nmj KW - phosphorylation N1 - CK2beta-MuSK interaction responsible for AChR clustering in NMJ RNAi CK2beta kills cells, not CK2alpha ! AU - Cheusova, Tatiana AU - Khan, Muhammad AU - Schubert, Steffen AU - Gavin, Anne-Claude AU - Buchou, Thierry AU - Jacob, Germaine AU - Sticht, Heinrich AU - Allende, Jorge AU - Boldyreff, Brigitte AU - Brenner, Hans AU - Hashemolhosseini, Said PY - 2006/07/01/ UR - http://dx.doi.org/10.1101/gad.375206 ER -