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AKT phosphorylates USP4. 30 / 31
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"AKT phosphorylates USP4, leading to USP4 relocalization to the membrane, reinforcing the pro-tumorigenic functions of TGFβ [ xref ]."
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"EGF enhances the deubiquitination of Rheb through AKT-dependent USP4 phosphorylation, leading to the release of Rheb from the TSC complex."
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"Similarly, phosphorylation of USP4 by AKT also leads to its redistribution from the nucleus to the cytoplasm, where it ultimately reaches the cell membrane to deubiquitylate the TFG-β receptor I [85] [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"USP4 also directly associated with AKT and became phosphorylated by AKT on a conserved Ser445 motif."
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"Phosphorylation of USP4 by AKT enhances the association of USP4 with cell surface TβRI, and USP4-mediated TβRI de-ubiquitylation ( xref )."
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"Furthermore, they demonstrate that AKT phosphorylation of USP4 enhances the binding of USP4 to USP15 and that overexpression of USP15 increases USP4 stability."
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"Upon growth factor stimulation, deubiquitinase USP4 was phosphorylated by AKT, resulting in the release of the inhibitory TSC complex from Rheb, which is essential for the activation of both Rheb and mTORC1."
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"Further, a genome-wide gain-of-function study revealed that AKT acts as a kinase for USP4 phosphorylation and phosphorylated USP4 moves into the cytoplasm from the nucleus."
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"USP4 is phosphorylated by AKT and translocated to the cytoplasm and membrane, where USP4 binds TβRI to deubiquitinate and protect it from damage ( xref )."
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"Moreover, this report showed that USP4 was phosphorylated by AKT, leading to increased USP4 membrane localization and promoting USP4 self association, leading to enhanced TGF-beta signalling."
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"These results indicate that Akt phosphorylates USP4 and regulates it subcellular localization by promoting USP4 to the membrane and cytoplasm."
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"Furthermore, the phosphorylation of USP4 by Akt was also required for it to associate with other DUBs to deubiquitylate the TGF-β receptors."
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"Moreover, this report showed that USP4 was phosphorylated by AKT, leading to increased USP4 membrane-localization and promoting USP4 self-association, leading to enhanced TGF-β signalling."
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"Interestingly, phosphorylated USP4 by AKT enhances the stability of TGF-β receptor type I (TGF-βRI) by preventing its ubiquitination, which is crucial for the activation of downstream TGF-β signaling pathways."
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"According to a previous study by Iyengar [XREF_BIBR], Akt promotes USP4 to enter the cell membrane and cytoplasm to phosphorylate USP4 and regulate its subcellular localization, and Akt phosphorylation of USP4 occurs by combining with other de-ubiquitinating enzymes (DUBs) to de-ubiquitinate the TGF-beta receptor [XREF_BIBR]."
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"Posttranslational modifications, apart from affecting DUB catalytic activity, have also been reported to affect the nuclear localization of DUBs. [ xref , xref , xref , xref , xref ] To illustrate, phosphorylation of USP4 by protein kinase B (PKB, also known as AKT) results in its redistribution from the nucleus to the cytoplasm, which enables USP4 to reach the cell membrane and deubiquitinate the transforming growth factor‐ β (TGF‐ β ) receptor I (T β R‐I). [ xref ] Furthermore, localization can also be indirectly modulated by changing the protein interactions that a DUB engages in ref. [ xref ] ."
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"According to a previous study by Iyengar [ xref ], Akt promotes USP4 to enter the cell membrane and cytoplasm to phosphorylate USP4 and regulate its subcellular localization, and Akt phosphorylation of USP4 occurs by combining with other de-ubiquitinating enzymes (DUBs) to de-ubiquitinate the TGF-β receptor [ xref ]."
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"Similarly, phosphorylation of USP4 by AKT also leads to its redistribution from the nucleus to the cytoplasm, where it ultimately reaches the cell membrane to deubiquitylate the TFG-β receptor I [85] [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"It has been reported that Src can induce activation of AKT, and that AKT can directly interact with and phosphorylate ubiquitin specific protease 4 (USP4), a deubiquitinating enzyme responsible for extending TGF-beta receptor I life on cell membranes by preventing its degradation."
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"Akt, a serine/threonine-specific protein kinase, phosphorylates USP4, which promotes its re-localization from the nucleus to the membrane, where it binds with TβRI."
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"Furthermore, they demonstrate that AKT phosphorylation of USP4 enhances the binding of USP4 to USP15 and that overexpression of USP15 increases USP4 stability."
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"Importantly, AKT (also known as protein kinase B), which has been associated with poor prognosis in breast cancer, directly associates with and phosphorylates USP4."
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"Furthermore, the phosphorylation of USP4 by Akt was also required for it to associate with other DUBs to deubiquitylate the TGF-beta receptors."
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"In contrast, Akt can phosphorylate the deubiquitinase USP4 that promotes RHEB deubiquitination thereby releasing RHEB from TSC [ xref ]."
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"For example, phosphorylation of USP4 by AKT activates and thus stabilizes this DUB, a process required for proper regulation of TGF-beta signaling during embryonic development (further discussed below) [XREF_BIBR, XREF_BIBR]."
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"In breast cancer, USP4 can be phosphorylated by AKT activation, with subsequent relocation to and stabilization of TβRI in the plasma membrane, indicating poor prognosis [ 20 ]."
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"For example, phosphorylation of USP4 by AKT activates and thus stabilizes this DUB, a process required for proper regulation of TGF-β signaling during embryonic development (further discussed below) [ xref , xref ]."
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"These results indicate that Akt phosphorylates USP4 and regulates it subcellular localization by promoting USP4 to the membrane and cytoplasm."
28425962
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"AKT phosphorylates USP4, leading to USP4 relocalization to the membrane, reinforcing the pro tumorigenic functions of TGFbeta [XREF_BIBR]."
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"Furthermore, the cell type or context dependent selectivity of one of these DUBs over the others (e.g. the AKT phosphorylation site in USP4 is not conserved in USP11 or USP15) is a possibility and needs to be investigated further."
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