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PMID:18602463

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Citation

Nonis, D, Schmidt, MH, van de Loo, S, Eich, F, Dikic, I, Nowock, J and Auburger, G (2008) Ataxin-2 associates with the endocytosis complex and affects EGF receptor trafficking. Cell. Signal. 20:1725-39

Abstract

Ataxin-2 is a novel protein, where the unstable expansion of an internal polyglutamine domain can cause the neurodegenerative disease Spinocerebellar Ataxia type 2 (SCA2). To elucidate its cellular function, we have used full-length ataxin-2 as bait in a yeast two-hybrid screen of human adult brain cDNA. As binding partners we found endophilin A1 and A3, two brain-expressed members of the endophilin A family involved in synaptic vesicle endocytosis. Co-immunoprecipitation studies confirmed the binding of these proteins as an endogenous complex in mouse brain. In vitro binding experiments narrowed the binding interfaces down to two proline-rich domains on ataxin-2, which interacted with the SH3 domain of endophilin A1/A3. Ataxin-2 and endophilin associated at the endoplasmic reticulum as well as at the plasma membrane as determined by immunofluorescence microscopy of transfected cell lines, and by centrifugation fractionation studies of mouse brain. Importantly, the pattern observed in transfected cells was conserved in rat hippocampal neurons. In the mouse brain, an association of ataxin-2 with endocytic proteins such as the adaptor CIN85 and the ubiquitin ligase c-Cbl was also demonstrated. GST pull-down assays showed ataxin-2 to directly interact with the SH3 domains A and C of CIN85 and with the SH3 domain of Src, a kinase activated after receptor stimulation. Functional studies demonstrated that ataxin-2 affects endocytic trafficking of the epidermal growth factor receptor (EGFR). Taken together, these data implicate ataxin-2 to play a role in endocytic receptor cycling.

Links

PubMed Online version:10.1016/j.cellsig.2008.05.018

Keywords

Acyltransferases/chemistry; Acyltransferases/metabolism; Adaptor Proteins, Signal Transducing/chemistry; Adaptor Proteins, Signal Transducing/metabolism; Amino Acid Sequence; Animals; Brain/metabolism; Catalysis; Cell Line; Cell Membrane/enzymology; Endocytosis; Endoplasmic Reticulum/enzymology; Humans; Mice; Molecular Sequence Data; Neoplasm Proteins/metabolism; Nerve Tissue Proteins/chemistry; Nerve Tissue Proteins/metabolism; Proline/metabolism; Protein Binding; Protein Structure, Tertiary; Protein Transport; Proto-Oncogene Proteins c-cbl/metabolism; Receptor, Epidermal Growth Factor/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:EGFR

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99700

F

Seeded From UniProt

complete

HUMAN:ATX2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99962

F

Seeded From UniProt

complete

HUMAN:ATX2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99963

F

Seeded From UniProt

complete

HUMAN:SH3G2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99700

F

Seeded From UniProt

complete

HUMAN:SH3G3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99700

F

Seeded From UniProt

complete

HUMAN:ATX2

involved_in

GO:0002091: negative regulation of receptor internalization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ATX2

enables

GO:0005154: epidermal growth factor receptor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P00533

F

Seeded From UniProt

complete

See also

References

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