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PMID:23455153

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Citation

Zhang, X, Zhang, J, Bauer, A, Zhang, L, Selinger, DW, Lu, CX and Ten Dijke, P (2013) Fine-tuning BMP7 signalling in adipogenesis by UBE2O/E2-230K-mediated monoubiquitination of SMAD6. EMBO J. 32:996-1007

Abstract

SMAD6 is a crucial feedback inhibitory regulator of bone morphogenetic protein (BMP)/SMAD signalling. Although little is known regarding the post-transcriptional modification of inhibitory SMADs and the mechanism by which their function is regulated. In this study, using a whole proteomic interaction screen for SMAD6, we identified a large putative E2 ubiquitin-conjugating enzyme UBE2O (E2-230K) as a novel interacting protein of SMAD6. We showed that UBE2O functions as an E2-E3 hybrid to monoubiquitinate SMAD6 at lysine 174 and that the cysteine 885 residue of human UBE2O is necessary for SMAD6 monoubiquitination. Inactivation of the SMAD6 monoubiquitination site specially potentiates the inhibitory ability of SMAD6 against BMP7-induced SMAD1 phosphorylation and transcriptional responses. We also found that UBE2O potentiated BMP7 signalling in a SMAD6-dependent manner. Addressing the molecular mechanism by which UBE2O and monoubiquitinated SMAD6 potentiate BMP7 signalling, we demonstrated that monoubiquitinated SMAD6 impairs the binding affinity of non-modified SMAD6 to the BMP type I receptor. Moreover, UBE2O and SMAD6 cooperated in the regulation of BMP7-induced adipogenesis.

Links

PubMed PMC3616286 Online version:10.1038/emboj.2013.38

Keywords

Adipogenesis/physiology; Animals; Bone Morphogenetic Protein 7/genetics; Bone Morphogenetic Protein 7/metabolism; Bone Morphogenetic Protein Receptors, Type I/genetics; Bone Morphogenetic Protein Receptors, Type I/metabolism; Hep G2 Cells; Humans; Mice; Mice, Knockout; Phosphorylation/physiology; Signal Transduction/physiology; Smad1 Protein/genetics; Smad1 Protein/metabolism; Smad6 Protein/genetics; Smad6 Protein/metabolism; Transcription, Genetic/physiology; Ubiquitin-Conjugating Enzymes/genetics; Ubiquitin-Conjugating Enzymes/metabolism; Ubiquitination/physiology

Significance

Annotations

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

MOUSE:SMAD6

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P36898

F

Seeded From UniProt

complete

MOUSE:SMAD6

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9C0C9

F

Seeded From UniProt

complete

MOUSE:SMAD7

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9C0C9

F

Seeded From UniProt

complete

MOUSE:BMR1B

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O35182

F

Seeded From UniProt

complete

HUMAN:UBE2O

involved_in

GO:0030513: positive regulation of BMP signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:UBE2O

involved_in

GO:0006513: protein monoubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:UBE2O

enables

GO:0004842: ubiquitin-protein transferase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:UBE2O

enables

GO:0061630: ubiquitin protein ligase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:UBE2O

enables

GO:0061631: ubiquitin conjugating enzyme activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:UBE2O

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O35182

F

Seeded From UniProt

complete

HUMAN:UBE2O

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O35253

F

Seeded From UniProt

complete

HUMAN:SMAD6

involved_in

GO:0045444: fat cell differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SMAD6

involved_in

GO:0030509: BMP signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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