Liprinalpha1 degradation by calcium/calmodulin-dependent protein kinase II regulates LAR receptor tyrosine phosphatase distribution and dendrite development.
Neural activity regulates dendrite and synapse development, but the underlying molecular mechanisms are unclear. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is an important sensor of synaptic activity, and the scaffold protein liprinalpha1 is involved in pre- and postsynaptic maturation. Here we show that synaptic activity can suppress liprinalpha1 protein level by two pathways: CaMKII-mediated degradation and the ubiquitin-proteasome system. In hippocampal neurons, liprinalpha1 mutants that are immune to CaMKII degradation impair dendrite arborization, reduce spine and synapse number, and inhibit dendritic targeting of receptor tyrosine phosphatase LAR, which is important for dendrite development. Thus, regulated degradation of liprinalpha1 is important for proper LAR receptor distribution, and could provide a mechanism for localized control of dendrite and synapse morphogenesis by activity and CaMKII.
Hoogenraad
Casper C
CC
The Picower Institute for Learning and Memory, RIKEN-MIT Neuroscience Research Center, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Feliu-Mojer
Monica I
MI
Spangler
Samantha A
SA
Milstein
Aaron D
AD
Dunah
Anthone W
AW
Hung
Albert Y
AY
Sheng
Morgan
M
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003712:Dendrites / Q000378:metabolism / Q000502:physiology*; D029721:Drosophila Proteins / Q000235:genetics; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D009024:Morphogenesis; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D011956:Receptors, Cell Surface / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics
C467323:APC2 protein, Drosophila; D048868:Adaptor Proteins, Signal Transducing; D029721:Drosophila Proteins; D009419:Nerve Tissue Proteins; C094398:PPFIA1 protein, human; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C516772:PTPRF protein, human; D017027:Protein Tyrosine Phosphatases; C516774:Ptprf protein, rat; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D046988:Proteasome Endopeptidase Complex