title: Proteasomal interactors control activities as diverse as the cell cycle and glutaminergic neurotransmission.
abstract: The six regulatory non-redundant ATPases in the base of the 19 S regulator of the 26 S proteasome belong to the AAA superfamily of ATPases. Yeast two-hybrid genetic screens, biochemical analyses and cell biological studies have identified and characterized new interactors of the human S6 (rpt3) and S8 (rpt6) ATPases of the 19 S regulator of the 26 S proteasome. The S6 ATPase interacts with gankyrin. This protein is found in purified human 26 S proteasomes and in a smaller complex(es) containing CDK4 and free S6 ATPase. Gankyrin overexpression causes the phosphorylation of the retinoblastoma protein (pRb) and the release of E2F transcription factor to trigger the expression of DNA synthesis genes. Gankyrin is oncogenic in nude mice and is overexpressed in hepatocellular carcinoma cells (HCCs). The S8 ATPase interacts with members of the large Homer-3 protein family. There are three Homer genes; the Homer 1 and 2 gene products control trafficking and calcium-store-related functions of metabotropic glutamate receptors (e.g. mGluR1alpha). Homer-3A11 by binding to the S8 ATPase brings mGluR1alpha to the 26 S proteasome for degradation. The degradation of mGluR1alpha is blocked by proteasomal inhibitors and by overexpression of the N-terminus of Homer which binds to the receptor. The S8 ATPase and mGluR1alpha are co-localized in Purkinje dendrites in rat cerebellum. The data are discussed in terms of the regulation of the cell cycle and glutaminergic receptor functions by the 26 S proteasome.
authors.affiliation: Laboratory of Intracellular Proteolysis, School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, U.K.
authors.forename: K
authors.initials: K
authors.lastname: Rezvani
authors.forename: M
authors.initials: M
authors.lastname: Mee
authors.forename: S
authors.initials: S
authors.lastname: Dawson
authors.forename: J
authors.initials: J
authors.lastname: McIlhinney
authors.forename: J
authors.initials: J
authors.lastname: Fujita
authors.forename: R J
authors.initials: RJ
authors.lastname: Mayer
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002453:Cell Cycle; D018076:DNA, Complementary; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005822:Genetic Vectors; D005973:Glutamine; D006801:Humans; D018377:Neurotransmitter Agents; D015513:Oncogene Proteins / Q000378:metabolism / Q000502:physiology; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D011518:Proto-Oncogene Proteins; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D020798:Two-Hybrid System Techniques
chemical_list: D018076:DNA, Complementary; D018377:Neurotransmitter Agents; D015513:Oncogene Proteins; C403591:PSMD10 protein, human; D011518:Proto-Oncogene Proteins; D018094:Receptors, Metabotropic Glutamate; D005973:Glutamine; D010450:Endopeptidases; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C119011:26S proteasome non-ATPase regulatory subunit 13; D000251:Adenosine Triphosphatases