title: USP15 regulates SMURF2 kinetics through C-lobe mediated deubiquitination.
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.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore.
authors.forename: Prasanna Vasudevan
authors.initials: PV
authors.lastname: Iyengar
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore.
authors.forename: Patrick
authors.initials: P
authors.lastname: Jaynes
authors.affiliation: Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, 08035 Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Rodon
authors.affiliation: Bioinformatics Institute (A*STAR), 30 Biopolis Street, 07-01 Matrix, 138671, Singapore.
authors.forename: Dilraj
authors.initials: D
authors.lastname: Lama
authors.affiliation: Deparment of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Kai Pong
authors.initials: KP
authors.lastname: Law
authors.affiliation: Deparment of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Yoon Pin
authors.initials: YP
authors.lastname: Lim
authors.affiliation: Bioinformatics Institute (A*STAR), 30 Biopolis Street, 07-01 Matrix, 138671, Singapore.|Department of Biological Sciences, National University of Singapore, 117543, Singapore.|School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637551, Singapore.
authors.forename: Chandra
authors.initials: C
authors.lastname: Verma
authors.affiliation: Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, 08035 Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Seoane
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore.|Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.
authors.forename: Pieter Johan Adam
authors.initials: PJ
authors.lastname: Eichhorn
mesh_terms: D000595:Amino Acid Sequence; D002465:Cell Movement; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008239:Lysine / Q000378:metabolism; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D064570:Ubiquitin-Specific Proteases / Q000502:physiology*; D054875:Ubiquitination
chemical_list: D016212:Transforming Growth Factor beta; C471641:SMURF2 protein, human; D044767:Ubiquitin-Protein Ligases; C579226:USP15 protein, human; D064570:Ubiquitin-Specific Proteases; D008239:Lysine