2. Signaling Pathways
  3. Cell Cycle/DNA Damage
  4. Deubiquitinase
  5. USP15 Isoform

USP15

USP15 (ubiquitin-specific peptidase 15) is a member of the ubiquitin-specific protease family that catalyzes deubiquitination through removal of ubiquitin chains and ubiquitin-substrate conjugates, thereby regulating ubiquitin-dependent cellular processes[1]. USP15 functions as a critical regulator of TGF-β signaling, where it counteracts ubiquitination-mediated degradation of type I TGF-β receptor (TβRI) and promotes receptor stability and downstream transcriptional responses[2][3][4]. Mechanistically, USP15 deubiquitinates both TβRI and receptor-regulated SMAD proteins, restoring SMAD transcriptional activity and supporting expression of TGF-β target genes[2][3][5]. Consequently, USP15 has been implicated in biological processes associated with tissue homeostasis, development, immunity, and cancer-related signaling pathways that depend on TGF-β activity[2][3]. In disease contexts, elevated USP15 expression or activity has been reported in multiple malignancies, including glioblastoma, breast cancer, and ovarian cancer, where enhanced TGF-β signaling may contribute to tumor progression[3]. Compared with related DU-family deubiquitinases, USP15 shares structural homology with USP4 and USP11 but exhibits distinct substrate regulation and signaling functions[6][5]. Notably, both USP15 and USP4 regulate TGF-β pathway components, yet USP15 acts through stabilization of TβRI and deubiquitination of receptor-regulated SMADs, whereas USP4 directly deubiquitinates TβRI to maintain receptor abundance at the plasma membrane[3][8]. For experimental applications, structurally characterized ubiquitin-variant inhibitors of USP15 have been developed, providing useful tools for investigating USP15-dependent signaling mechanisms and validating therapeutic hypotheses in disease models[9].

USP15 Related Products (2):

Cat. No. Product Name Effect Purity
  • HY-180171
    USP11-IN-1
    		Inhibitor
    USP11-IN-1 (Compound 26) is a selective ubiquitin-specific protease 11 (USP11) inhibitor with an IC50 of 10.9 μM. USP11-IN-1 shows IC50 values of 18.1 and >500 μM for USP4 (SI = 1.7 fold) and USP15 (SI > 100 fold). USP11-IN-1 can be used for the research of USP11-related malignant tumors.
  • HY-184273
    TH-407a
    		Inhibitor
    TH-407a is an orally active and selective USP15 inhibitor with an IC50 of 0.76 μM. As an allosteric modulator, TH-407a binds to a non-catalytic site to block deubiquitinating activity. TH-407a inhibits cell growth, proliferation, clonogenicity and migration, regulates the p53 signaling pathway, and reduces the stability of PARP1. TH-407a exhibits anti-tumor activity in breast cancer xenograft mouse models. TH-407a can be used for the research of breast cancer.