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Title: USP15 regulates SMURF2 kinetics through C-lobe mediated deubiquitination
Authors: Iyengar, P.V 
Jaynes, P 
Rodon, L
Lama, D
Law, K.P 
Lim, Y.P 
Verma, C 
Seoane, J
Eichhorn, P.J.A 
Keywords: deubiquitinase
SMURF2 protein, human
transforming growth factor beta
ubiquitin protein ligase
USP15 protein, human
amino acid sequence
cell motion
HEK293 cell line
protein degradation
protein tertiary structure
signal transduction
Amino Acid Sequence
Cell Movement
HEK293 Cells
Protein Structure, Tertiary
Signal Transduction
Transforming Growth Factor beta
Ubiquitin-Protein Ligases
Ubiquitin-Specific Proteases
Issue Date: 2015
Citation: Iyengar, P.V, Jaynes, P, Rodon, L, Lama, D, Law, K.P, Lim, Y.P, Verma, C, Seoane, J, Eichhorn, P.J.A (2015). USP15 regulates SMURF2 kinetics through C-lobe mediated deubiquitination. Scientific Reports 5 : 14733. ScholarBank@NUS Repository.
Abstract: Ubiquitin modification of the TGF-β pathway components is emerging as a key mechanism of TGF-β pathway regulation. To limit TGF-β responses, TGF-β signaling is regulated through a negative feedback loop whereby the E3 ligase SMURF2 targets the TGF-β receptor (TβR) complex for ubiquitin-mediated degradation. Counteracting this process, a number of deubiquitinating (DUBs) enzymes have recently been identified that deubiquitinate and stabilize the TβR. However the precise mechanism by which these DUBs act on TβR function remains poorly defined. Here, we demonstrate that apart from targeting the TβR complex directly, USP15 also deubiquitinates SMURF2 resulting in enhanced TβR stability and downstream pathway activation. Through proteomic analysis, we show that USP15 modulates the ubiquitination of Lys734, a residue required for SMURF2 catalytic activity. Our results show that SMURF2 is a critical target of USP15 in the TGF-β pathway and may also explain how USP15 and SMURF2 target multiple complementary protein complexes in other pathways.
Source Title: Scientific Reports
ISSN: 2045-2322
DOI: 10.1038/srep14733
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