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Ubiquitin-specific proteases as therapeutic targets for the treatment of breast cancer.

Pal A, Donato NJ - Breast Cancer Res. (2014)

Bottom Line: Availability of new tools capable of sensitive detection of gene mutations and aberrant expression of genes and proteins coupled with gene-specific knockdown and silencing protocols have provided insight into the previously unexplored ubiquitin regulatory process within these tumors.Ubiquitin-specific proteases are one class of enzymes with protein deubiquitinating activity, making up the majority of protein deubiquitinating diversity within mammalian cells.In this report, we summarize the involvement of this class of enzymes in breast cancer signaling and cell regulation and illustrate the potential for additional studies to define novel targets and approaches in breast cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA.

ABSTRACT
Key mediators of signaling pathways in breast cancer involve post-translational protein modification, primarily mediated through phosphorylation and ubiquitination. While previous studies focused on phosphorylation events, more recent analysis suggests that ubiquitin plays a parallel and equally important role in several signaling and cell regulatory events in breast cancer. Availability of new tools capable of sensitive detection of gene mutations and aberrant expression of genes and proteins coupled with gene-specific knockdown and silencing protocols have provided insight into the previously unexplored ubiquitin regulatory process within these tumors. Ubiquitin-specific proteases are one class of enzymes with protein deubiquitinating activity, making up the majority of protein deubiquitinating diversity within mammalian cells. Ubiquitin-specific proteases are also emerging as potential therapeutic targets in many diseases, including cancer. In this report, we summarize the involvement of this class of enzymes in breast cancer signaling and cell regulation and illustrate the potential for additional studies to define novel targets and approaches in breast cancer therapy.

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Regulation of transforming growth factor beta signaling by ubiquitin-specific proteases in breast cancer. Ubiquitin-specific proteases (USPs) overexpressed and implicated in breast cancer regulate transforming growth factor beta (TGFβ) signaling at different levels in the signaling cascade. USP15, USP11 and USP4 inhibit TGFβ type I receptor degradation by preventing proteasomal destruction through deubiquitination and stabilization of TGFβ type I receptor, resulting in enhancement of TGFβ signaling. USP11 directly binds to the type I receptor whereas USP15 binds the receptor through complex formation with Smad7–Smurf2. USP4 also binds directly to the type I receptor but only when phosphorylated by AKT kinase. USP4 is phosphorylated in the nucleus by AKT kinase. Phosphorylated USP4 translocates to the membrane, binds and stabilizes type I receptor. TGFβ signaling can also be regulated at the coreceptor Smad level by USP9X. Smad4 mono-ubiquitination at K519 inhibits its binding with phospho-Smad2 and thus inhibits Smad 4 and TGFβ signaling. Through its deubiquitinating activity, US9X reverses mono-ubiquitination and stabilizes Smad4, resulting in the sustained activation of TGFβ signaling. P, phosphorylation; TF, transcription factor; Ub, ubiquitin.
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Fig1: Regulation of transforming growth factor beta signaling by ubiquitin-specific proteases in breast cancer. Ubiquitin-specific proteases (USPs) overexpressed and implicated in breast cancer regulate transforming growth factor beta (TGFβ) signaling at different levels in the signaling cascade. USP15, USP11 and USP4 inhibit TGFβ type I receptor degradation by preventing proteasomal destruction through deubiquitination and stabilization of TGFβ type I receptor, resulting in enhancement of TGFβ signaling. USP11 directly binds to the type I receptor whereas USP15 binds the receptor through complex formation with Smad7–Smurf2. USP4 also binds directly to the type I receptor but only when phosphorylated by AKT kinase. USP4 is phosphorylated in the nucleus by AKT kinase. Phosphorylated USP4 translocates to the membrane, binds and stabilizes type I receptor. TGFβ signaling can also be regulated at the coreceptor Smad level by USP9X. Smad4 mono-ubiquitination at K519 inhibits its binding with phospho-Smad2 and thus inhibits Smad 4 and TGFβ signaling. Through its deubiquitinating activity, US9X reverses mono-ubiquitination and stabilizes Smad4, resulting in the sustained activation of TGFβ signaling. P, phosphorylation; TF, transcription factor; Ub, ubiquitin.

Mentions: DUBs can regulate TGFβ signaling at the receptor, receptor-Smad or coreceptor-Smad level (Figure 1). USP11 and USP15 regulate TGFβ signaling through modulation of TGFβ receptor I levels [20],[21]. USP11 binds to Smad7, which then recruits USP11 to TGFβ receptor I where it interacts, deubiquitinates and stabilizes TGFβ receptor I to sustain Smad-mediated TGFβ signaling [20]. USP15 binds to the Smad7–SMURF2 complex, which recruits USP15 to TGFβ receptor I and stabilizes it without direct binding [21]. USP4 is reported to directly interact and deubiquitinate TGFβ receptor I to regulate TGFβ signaling [22]. Inhibition of USP11, USP4 and USP15 blocks TGFβ-mediated EMT and invasion in breast cancer [20]-[22]. Interestingly, AKT directly interacts and phosphorylates USP4, which then translocates from the nucleus to the plasma membrane where it stabilizes TGFβ receptor I through direct interaction [22]. AKT activation is associated with poor prognosis in breast cancer and inhibiting USP4 suppresses AKT-mediated breast cancer cell migration [22]. USP4 has thus been proposed as an important determinant of crosstalk between TGFβ and AKT signaling in breast cancer.Figure 1


Ubiquitin-specific proteases as therapeutic targets for the treatment of breast cancer.

Pal A, Donato NJ - Breast Cancer Res. (2014)

Regulation of transforming growth factor beta signaling by ubiquitin-specific proteases in breast cancer. Ubiquitin-specific proteases (USPs) overexpressed and implicated in breast cancer regulate transforming growth factor beta (TGFβ) signaling at different levels in the signaling cascade. USP15, USP11 and USP4 inhibit TGFβ type I receptor degradation by preventing proteasomal destruction through deubiquitination and stabilization of TGFβ type I receptor, resulting in enhancement of TGFβ signaling. USP11 directly binds to the type I receptor whereas USP15 binds the receptor through complex formation with Smad7–Smurf2. USP4 also binds directly to the type I receptor but only when phosphorylated by AKT kinase. USP4 is phosphorylated in the nucleus by AKT kinase. Phosphorylated USP4 translocates to the membrane, binds and stabilizes type I receptor. TGFβ signaling can also be regulated at the coreceptor Smad level by USP9X. Smad4 mono-ubiquitination at K519 inhibits its binding with phospho-Smad2 and thus inhibits Smad 4 and TGFβ signaling. Through its deubiquitinating activity, US9X reverses mono-ubiquitination and stabilizes Smad4, resulting in the sustained activation of TGFβ signaling. P, phosphorylation; TF, transcription factor; Ub, ubiquitin.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4384352&req=5

Fig1: Regulation of transforming growth factor beta signaling by ubiquitin-specific proteases in breast cancer. Ubiquitin-specific proteases (USPs) overexpressed and implicated in breast cancer regulate transforming growth factor beta (TGFβ) signaling at different levels in the signaling cascade. USP15, USP11 and USP4 inhibit TGFβ type I receptor degradation by preventing proteasomal destruction through deubiquitination and stabilization of TGFβ type I receptor, resulting in enhancement of TGFβ signaling. USP11 directly binds to the type I receptor whereas USP15 binds the receptor through complex formation with Smad7–Smurf2. USP4 also binds directly to the type I receptor but only when phosphorylated by AKT kinase. USP4 is phosphorylated in the nucleus by AKT kinase. Phosphorylated USP4 translocates to the membrane, binds and stabilizes type I receptor. TGFβ signaling can also be regulated at the coreceptor Smad level by USP9X. Smad4 mono-ubiquitination at K519 inhibits its binding with phospho-Smad2 and thus inhibits Smad 4 and TGFβ signaling. Through its deubiquitinating activity, US9X reverses mono-ubiquitination and stabilizes Smad4, resulting in the sustained activation of TGFβ signaling. P, phosphorylation; TF, transcription factor; Ub, ubiquitin.
Mentions: DUBs can regulate TGFβ signaling at the receptor, receptor-Smad or coreceptor-Smad level (Figure 1). USP11 and USP15 regulate TGFβ signaling through modulation of TGFβ receptor I levels [20],[21]. USP11 binds to Smad7, which then recruits USP11 to TGFβ receptor I where it interacts, deubiquitinates and stabilizes TGFβ receptor I to sustain Smad-mediated TGFβ signaling [20]. USP15 binds to the Smad7–SMURF2 complex, which recruits USP15 to TGFβ receptor I and stabilizes it without direct binding [21]. USP4 is reported to directly interact and deubiquitinate TGFβ receptor I to regulate TGFβ signaling [22]. Inhibition of USP11, USP4 and USP15 blocks TGFβ-mediated EMT and invasion in breast cancer [20]-[22]. Interestingly, AKT directly interacts and phosphorylates USP4, which then translocates from the nucleus to the plasma membrane where it stabilizes TGFβ receptor I through direct interaction [22]. AKT activation is associated with poor prognosis in breast cancer and inhibiting USP4 suppresses AKT-mediated breast cancer cell migration [22]. USP4 has thus been proposed as an important determinant of crosstalk between TGFβ and AKT signaling in breast cancer.Figure 1

Bottom Line: Availability of new tools capable of sensitive detection of gene mutations and aberrant expression of genes and proteins coupled with gene-specific knockdown and silencing protocols have provided insight into the previously unexplored ubiquitin regulatory process within these tumors.Ubiquitin-specific proteases are one class of enzymes with protein deubiquitinating activity, making up the majority of protein deubiquitinating diversity within mammalian cells.In this report, we summarize the involvement of this class of enzymes in breast cancer signaling and cell regulation and illustrate the potential for additional studies to define novel targets and approaches in breast cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA.

ABSTRACT
Key mediators of signaling pathways in breast cancer involve post-translational protein modification, primarily mediated through phosphorylation and ubiquitination. While previous studies focused on phosphorylation events, more recent analysis suggests that ubiquitin plays a parallel and equally important role in several signaling and cell regulatory events in breast cancer. Availability of new tools capable of sensitive detection of gene mutations and aberrant expression of genes and proteins coupled with gene-specific knockdown and silencing protocols have provided insight into the previously unexplored ubiquitin regulatory process within these tumors. Ubiquitin-specific proteases are one class of enzymes with protein deubiquitinating activity, making up the majority of protein deubiquitinating diversity within mammalian cells. Ubiquitin-specific proteases are also emerging as potential therapeutic targets in many diseases, including cancer. In this report, we summarize the involvement of this class of enzymes in breast cancer signaling and cell regulation and illustrate the potential for additional studies to define novel targets and approaches in breast cancer therapy.

Show MeSH
Related in: MedlinePlus