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PMID:17512523

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Citation

Lim, MK, Kawamura, T, Ohsawa, Y, Ohtsubo, M, Asakawa, S, Takayanagi, A and Shimizu, N (2007) Parkin interacts with LIM Kinase 1 and reduces its cofilin-phosphorylation activity via ubiquitination. Exp. Cell Res. 313:2858-74

Abstract

Mutations in the PARKIN (PARK2) gene have been found in the majority of early-onset familial Parkinson's disease (PD) patients with autosomal recessive juvenile parkinsonism (ARJP). Parkin protein functions as an ubiquitin (E3) ligase that targets specific proteins for degradation in the 26S proteasome. Here, based on a mass spectrometry analysis of the human dopaminergic neuroblastoma-derived cell line SH-SY5Y that over-expresses parkin, we found that parkin may suppress cofilin phosphorylation. LIM Kinase 1 (LIMK1) is the upstream protein that phosphorylates cofilin, an actin depolymerizing protein. Thus, we postulated a possible connection between parkin and LIMK1. Our studies in other cell lines, using co-transfection assays, demonstrated that LIMK1 and parkin bind each other. LIMK1 also interacted with previously known parkin interactors Hsp70 and CHIP. Parkin enhanced LIMK1-ubiquitination in the human neuroblastoma-derived BE(2)-M17 cell line, but not in the human embryonic kidney-derived HEK293 cell line. In fact, parkin-over-expression reduced the level of LIMK1-induced phosphocofilin in the BE(2)-M17 cells but not in the HEK293 cells. Additionally, in simian kidney-derived COS-7 cells, parkin-over-expression reduced LIMK1-induced actin filament accumulation. LIMK1 in cultured cells regulates parkin reversibly: LIMK1 did not phosphorylate parkin but LIMK1 overexpression reduced parkin self-ubiquitination in vitro and in HEK293 cells. Furthermore, in the cells co-transfected with parkin and p38, LIMK1 significantly decreased p38-ubiquitination by parkin. These findings demonstrate a cell-type dependent functional interaction between parkin and LIMK1 and provide new evidence that links parkin and LIMK1 in the pathogenesis of familial PD.

Links

PubMed Online version:10.1016/j.yexcr.2007.04.016

Keywords

Actin Cytoskeleton/metabolism; Animals; COS Cells; Cell Line; Cercopithecus aethiops; Cofilin 1/metabolism; HSP70 Heat-Shock Proteins/metabolism; Humans; Lim Kinases; Parkinson Disease/enzymology; Phosphorylation; Protein Interaction Mapping; Protein Kinases/analysis; Protein Kinases/metabolism; Protein Structure, Tertiary; Ubiquitin/metabolism; Ubiquitin-Protein Ligases/analysis; Ubiquitin-Protein Ligases/metabolism

Significance

Annotations

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

HUMAN:PRKN

enables

GO:0030165: PDZ domain binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P53667

F

Seeded From UniProt

complete

HUMAN:PRKN

enables

GO:0019900: kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P53667

F

Seeded From UniProt

complete

HUMAN:PRKN

involved_in

GO:0051865: protein autoubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PRKN

involved_in

GO:0032232: negative regulation of actin filament bundle assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PRKN

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PRKN

involved_in

GO:0001933: negative regulation of protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:LIMK1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9UNE7

F

Seeded From UniProt

complete

HUMAN:LIMK1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O60260

F

Seeded From UniProt

complete

HUMAN:LIMK1

involved_in

GO:0032233: positive regulation of actin filament bundle assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:LIMK1

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:LIMK1

enables

GO:0031072: heat shock protein binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:LIMK1

involved_in

GO:0006468: protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:LIMK1

involved_in

GO:0051444: negative regulation of ubiquitin-protein transferase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CHIP

enables

GO:0019900: kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P53667

F

Seeded From UniProt

complete

HUMAN:PRKN2

involved_in

GO:0051865: protein autoubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PRKN2

involved_in

GO:0032232: negative regulation of actin filament bundle assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PRKN2

enables

GO:0030165: PDZ domain binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P53667

F

Seeded From UniProt

complete

HUMAN:PRKN2

enables

GO:0019900: kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P53667

F

Seeded From UniProt

complete

HUMAN:PRKN2

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PRKN2

involved_in

GO:0001933: negative regulation of protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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