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PMID:12049732

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Citation

Lu, Z, Xu, S, Joazeiro, C, Cobb, MH and Hunter, T (2002) The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2. Mol. Cell 9:945-56

Abstract

ERK1/2 MAP kinases are important regulators in cellular signaling, whose activity is normally reversibly regulated by threonine-tyrosine phosphorylation. In contrast, we have found that stress-induced ERK1/2 activity is downregulated by ubiquitin/proteasome-mediated degradation of ERK1/2. The PHD domain of MEKK1, a RING finger-like structure, exhibited E3 ubiquitin ligase activity toward ERK2 in vitro and in vivo. Moreover, both MEKK1 kinase activity and the docking motif on ERK1/2 were involved in ERK1/2 ubiquitination. Significantly, cells expressing ERK2 with the docking motif mutation were resistant to sorbitol-induced apoptosis. Therefore, MEKK1 functions not only as an upstream activator of the ERK and JNK through its kinase domain, but also as an E3 ligase through its PHD domain, providing a negative regulatory mechanism for decreasing ERK1/2 activity.

Links

PubMed

Keywords

3T3 Cells; Amino Acid Sequence; Animals; Blood; Cysteine Endopeptidases/metabolism; Down-Regulation; Enzyme Activation; Epidermal Growth Factor/metabolism; Humans; Ligases/metabolism; MAP Kinase Kinase Kinase 1; Mice; Mitogen-Activated Protein Kinase 1/genetics; Mitogen-Activated Protein Kinase 1/metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases/metabolism; Molecular Sequence Data; Multienzyme Complexes/metabolism; Mutagenesis, Site-Directed; Phosphorylation; Proteasome Endopeptidase Complex; Protein-Serine-Threonine Kinases/chemistry; Protein-Serine-Threonine Kinases/metabolism; Rats; Sorbitol/metabolism; Structure-Activity Relationship; Transfection; Tumor Cells, Cultured; Ubiquitin-Protein Ligases; Ubiquitins/metabolism

Significance

Annotations

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

RAT:M3K1

involved_in

GO:0000209: protein polyubiquitination

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:M3K1

involved_in

GO:0006511: ubiquitin-dependent protein catabolic process

ECO:0000316: genetic interaction evidence used in manual assertion

RGD:70500

P

Seeded From UniProt

complete

RAT:M3K1

enables

GO:0004842: ubiquitin-protein transferase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:M3K1

involved_in

GO:0046777: protein autophosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:M3K1

enables

GO:0051019: mitogen-activated protein kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:70500

F

Seeded From UniProt

complete

RAT:MK01

enables

GO:0031435: mitogen-activated protein kinase kinase kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:620966

F

Seeded From UniProt

complete


See also

References

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