The E3 Ligase TTC3 Facilitates Ubiquitination and Degradation of Phosphorylated Akt
The E3 Ligase TTC3 Facilitates Ubiquitination and Degradation of Phosphorylated Akt
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DOI：
10.1016/j.devcel.2009.09.007
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发表时间：
2009-12-15
影响因子：
11.8
通讯作者：
Noguchi, Masayuki
中科院分区：
文献类型：
--
作者：
Suizu, Futoshi;Hiramuki, Yosuke;Noguchi, Masayuki
丝氨酸苏氨酸激酶Akt是一种核心的生存因子，是多种人类疾病的基础。虽然调节磷酸化和去磷酸化已被充分记录，其他翻译后机制，调节AM活性仍不清楚。我们在这里表明，tetratricopeptide repeat domain 3（TTC 3）是一种E3连接酶，与Akt相互作用。TTC 3包含一个典型的RING指基序，一对四肽基序，一个假定的Akt磷酸化位点和核定位信号，并由21号染色体上唐氏综合征（DS）关键区域内的基因编码。TTC 3是Akt特异性E3连接酶，其结合磷酸化Akt并促进其在细胞核内的泛素化和降解。此外，DS细胞表现出升高的TTC 3表达、降低的磷酸化Akt和在G（2）M期的积累，这可以被TTC 3 siRNA或Myr-Akt逆转。因此，TTC 3和Akt之间的相互作用可能有助于DS的临床症状。
The serine threonine kinase Akt is a core survival factor that underlies a variety of human diseases. Although regulatory phosphorylation and dephosphorylation have been well documented, the other posttranslational mechanisms that modulate AM activity remain unclear. We show here that tetratricopeptide repeat domain 3 (TTC3) is an E3 ligase that interacts with Akt. TTC3 contains a canonical RING finger motif, a pair of tetratricopeptide motifs, a putative Akt phosphorylation site, and nuclear localization signals, and is encoded by a gene within the Down syndrome (DS) critical region on chromosome 21. TTC3 is an Akt-specific E3 ligase that binds to phosphorylated Akt and facilitates its ubiquitination and degradation within the nucleus. Moreover, DS cells exhibit elevated TTC3 expression, reduced phosphorylated Akt, and accumulation in the G(2)M phase, which can be reversed by TTC3 siRNA or Myr-Akt. Thus, interaction between TTC3 and Akt may contribute to the clinical symptoms of DS.