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  • In normal cells the apoptotic stimuli


    In normal cells, the apoptotic stimuli lower the expression level of antiapoptotic proteins by increasing turnover rate and preventing the constant degradation of proapoptotic proteins. Thus, the dysregulation of anti-/pro-apoptotic proteins will confer the survival of cancer mst2 via enhancing the degradation of proapoptotic proteins or stabilizing the antiapoptotic proteins. Recent studies on the molecular and cellular functions of different linkage types of ubiquitin chains have revealed that not only proteasome-dependent protein degradation, which is the classical function of ubiquitination, but also signaling roles are played by ubiquitin chains, especially in the regulation of apoptosis signaling cascade (Fig. 3).
    DUBs targeting therapeutics Specific mechanisms of deubiquitinating enzymes in various diseases have been described. Research should be concentrated on discovering an inhibitor on DUB\'s enzyme activity or antagonist which binds the substrates for therapy of cancer and other diseases (Table 2). While growing numbers of drugs have been developed to inhibit or antagonize DUBs, none of these have yet entered clinical trials.
    Conflict of interest statement
    Acknowledgment We thank all members from Wan laboratory for critical reading and discussion of our manuscript. We apologize to colleagues in the field whose work was not included due to space limitation. This work is supported by NIH grant CA154695, CA202948 and CA202963.
    Introduction The TGFβ family of cytokines comprises some 40 members including the bone morphogenetic protein (BMP) and controls a plethora of context-dependent cellular processes including proliferation, differentiation, extracellular matrix production, motility, survival and fate. Abnormal TGFβ signalling is linked to the manifestation of multiple human diseases, including fibrosis, immune disorders and cancer [1], [2], [3], [4]. TGFβ signalling is initiated when the ligands bind to a pair of cognate receptor serine/threonine protein kinases (termed type I and type II) on the cell surface. This triggers the phosphorylation of intracellular receptor regulated SMAD transcription factors (R-SMADs) by type I receptor kinases [5]. TGFβ ligands are divided into two subfamilies: the TGFβ subfamily, which primarily signals through the phosphorylation of SMADs 2 and 3, and the BMP subfamily, which signals through SMADs 1/5/8 [5] (Fig. 1). In the canonical pathway, the phosphorylated R-SMADs interact with SMAD4 and translocate to the nucleus, where together with other co-factors they regulate the transcription of over 500 target genes [5], [6], [7]. The context-dependent transcriptional programme driven by the TGFβ signals modulates cell behaviour [8], [9], [10]. The powerful action of TGFβ cytokines in cells and tissues is tightly regulated. Complex biochemical mechanisms have evolved to intricately control the extent, duration and potency of signalling in response to TGFβ cytokines. From secreted molecules that act as ligand traps to eventual transcriptional events that provide positive or negative feedback, complex regulatory inputs establish a dynamic fine-tuning of the TGFβ pathway [11], [12]. Regulation is also achieved through the addition or removal of post-translational modifications, such as phosphorylation and ubiquitylation, on core protein components of the TGFβ signalling pathway that alters their activity or stability [13], [14]. The regulatory inputs collectively shape and define the nature of cellular responses to TGFβ/BMP signals in diverse biological processes and contexts. Understanding the molecular details of how TGFβ signalling is regulated in cells could be key to unravelling new opportunities for therapeutic intervention against diseases associated with abnormal signalling. Reversible ubiquitylation of key components of the TGFβ pathway, including the type I TGFβ/BMP receptor kinases and SMADs, is known to play a critical role in regulating the outcome of TGFβ signalling [14], [15], [16], [17], [18], [19]. Much is known about the roles of various E3 ubiquitin ligases in regulating their stability. However, investigations into the regulation of the TGFβ/BMP pathways by DUBs primarily constitute recent progress and are still emerging.