USP15 regulates SMURF2 kinetics through C-lobe mediated deubiquitination
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Ubiquitin modification of the TGF-ß pathway components is emerging as a key mechanism of TGF-ß pathway regulation. To limit TGF-ß responses, TGF-ß signaling is regulated through a negative feedback loop whereby the E3 ligase SMURF2 targets the TGF-ß receptor (TßR) complex for ubiquitin-mediated degradation. Counteracting this process, a number of deubiquitinating (DUBs) enzymes have recently been identified that deubiquitinate and stabilize the TßR. However the precise mechanism by which these DUBs act on TßR function remains poorly defined. Here, we demonstrate that apart from targeting the TßR complex directly, USP15 also deubiquitinates SMURF2 resulting in enhanced TßR 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-ß pathway and may also explain how USP15 and SMURF2 target multiple complementary protein complexes in other pathways.
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Kit Leng Lui, S.; Iyengar, P.; Jaynes, P.; Isa, Z.; Pang, B.; Tan, T.; Eichhorn, Pieter (2017)© 2017 The Authors. Published under the terms of the CC BY 4.0 license The amplitude of transforming growth factor-ß (TGF-ß) signal is tightly regulated to ensure appropriate physiological responses. As part of negative ...
Jaynes, P.W.; Iyengar, P.V.; Lui, S.K.L.; Tan, T.Z.; Vasilevski, Natali; Wright, Sarah Christine Elizabeth; Verdile, Giuseppe ; Jeyasekharan, A.D.; Eichhorn, Pieter (2020)© 2020, The Author(s). Systematic control of the transforming growth factor-β (TGFβ) pathway is essential to keep the amplitude and the intensity of downstream signalling at appropriate levels. Ubiquitination plays a ...
Teyra, J.; Singer, A.; Schmitges, F.; Jaynes, P.; Kit Leng Lui, S.; Polyak, M.; Fodil, N.; Krieger, J.; Tong, J.; Schwerdtfeger, C.; Brasher, B.; Ceccarelli, DFJ ; Moffat, J.; Sicheri, F.; Moran, M.; Gros, P.; Eichhorn, Pieter ; Lenter, M.; Boehmelt, G.; Sidhu, S. (2019)The multi-domain deubiquitinase USP15 regulates diverse eukaryotic processes and has been implicated in numerous diseases. We developed ubiquitin variants (UbVs) that targeted either the catalytic domain or each of three ...