Abstract 4970: USP15 regulates SMURF2 kinetics through C-lobe mediated deubiquitination

Abstract

Abstract Transforming growth factor-β (TGFβ) is a multifunctional cytokine that acts as a tumour suppressor in normal cells and as an oncogene in advanced tumour cells. In the later scenario, TGFβ signaling enhances pro-invasive and pro-metastatic properties of the cancer cell. 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 TBR 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. Citation Format: Pieter J.A. Eichhorn, Prasanna Iyengar, Patrick Jaynes, Chandra Verma. USP15 regulates SMURF2 kinetics through C-lobe mediated deubiquitination. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4970. doi:10.1158/1538-7445.AM2015-4970