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Description:
Cyclin-dependent kinase 5 (Cdk5) and its activator p35 have been implicated in drug addiction, neurodegenerative diseases such as Alzheimer's, learning and memory, and synapse maturation and plasticity. However, the molecular mechanisms by which Cdk5 regulates synaptic plasticity are still unclear. PSD-95 is a major postsynaptic scaffolding protein of glutamatergic synapses that regulates synaptic strength and plasticity. PSD-95 is ubiquitinated by the ubiquitin E3 ligase Mdm2, and rapid and transient PSD-95 ubiquitination has been implicated in NMDA receptor-induced AMPA receptor endocytosis. Here we demonstrate that genetic or pharmacological reduction of Cdk5 activity increases the interaction of Mdm2 with PSD-95 and enhances PSD-95 ubiquitination without affecting PSD-95 protein levels in vivo in mice, suggesting a nonproteolytic function of ubiquitinated PSD-95 at synapses. We show that PSD-95 ubiquitination correlates with increased interaction with β-adaptin, a subunit of the clathrin adaptor protein complex AP-2. This interaction is increased by genetic reduction of Cdk5 activity or NMDA receptor stimulation and is dependent on Mdm2. Together these results support a function for Cdk5 in regulating PSD-95 ubiquitination and its interaction with AP-2 and suggest a mechanism by which PSD-95 may regulate NMDA receptor-induced AMPA receptor endocytosis.
Publications:
Bianchetta MJ, Lam TT, Jones SN, Morabito MA. (2011) Cyclin-dependent kinase 5 regulates PSD-95 ubiquitination in neurons. J Neurosci. 2011 Aug 17;31(33):12029-35. PubMed
Acknowledgement: This work was supported by NIH/NIDA Grants R01DA019451 to M.A.M., R01CA077735 to S.N.J., and 1P30DA018343 to the Yale/NIDA Neuroproteomics Center. We thank Drs. L.-H. Tsai and P. Giusti for the generous contribution of p35 knock-out mice.
Blib File: PSD95_MDM2_KOs_Phospho_and_Ubi.blib
24 results available, displaying 1 to 10.[First/Prev] 1, 2, 3 [Next/Last]
Analysis Type Sample Name Search Engine Database Date User/PI
LCMS MDM2_1S_TiO2_ENandFT info resources MASCOT SwissProt_2012_08.fasta 2012-10-05 12:26:01.0 Maria Morabito/Maria Morabito
LCMS MDM2_1S_Ubi_ENandFT info resources MASCOT SwissProt_2012_08.fasta 2012-10-05 12:32:53.0 Maria Morabito/Maria Morabito
LCMS MDM2_1_TiO2_ENandFT info resources MASCOT SwissProt_2012_08.fasta 2012-09-25 11:53:49.0 Maria Morabito/Maria Morabito
LCMS MDM2_1_Ubi_ENandFT info resources MASCOT SwissProt_2012_08.fasta 2012-09-25 12:02:27.0 Maria Morabito/Maria Morabito
LCMS MDM2_2S_TiO2_ENandFT info resources MASCOT SwissProt_2012_08.fasta 2012-10-05 12:37:19.0 Maria Morabito/Maria Morabito
LCMS MDM2_2S_Ubi_ENandFT info resources MASCOT SwissProt_2012_08.fasta 2012-10-05 12:45:17.0 Maria Morabito/Maria Morabito
LCMS MDM2_2_TiO2_ENandFT info resources MASCOT SwissProt_2012_08.fasta 2012-09-25 12:10:35.0 Maria Morabito/Maria Morabito
LCMS MDM2_2_Ubi_ENandFT info resources MASCOT SwissProt_2012_08.fasta 2012-09-25 12:19:39.0 Maria Morabito/Maria Morabito
LCMS P53_1S_TiO2_ENandFT info resources MASCOT SwissProt_2012_08.fasta 2012-10-05 11:56:29.0 Maria Morabito/Maria Morabito
LCMS P53_1S_Ubi_ENandFT info resources MASCOT SwissProt_2012_08.fasta 2012-10-05 12:06:25.0 Maria Morabito/Maria Morabito
DownLoad Peptide Summary pep_score > pep_homology
DownLoad Peptide Summary (all peptides with protein ids)


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Updated 21 Mar 2014 9:03