磷酸化事件的层次顺序促使Cdc25A发生依赖于βTrCP的降解。

Hierarchical order of phosphorylation events commits Cdc25A to betaTrCP-dependent degradation.

作者信息

Donzelli Maddalena, Busino Luca, Chiesa Massimo, Ganoth Dvora, Hershko Avram, Draetta Giulio F

机构信息

European Institute of Oncology, Milan, Italy.

出版信息

Cell Cycle. 2004 Apr;3(4):469-71. Epub 2004 Apr 1.

PMID:14752276

Abstract

We have recently demonstrated that regulation of Cdc25A protein abundance during S phase and in response to DNA damage is mediated by SCF(betaTrCP) activity. Based on sequence homology of known betaTrCP substrates, we found that Cdc25A contains a conserved motif (DSG), phosphorylation of which is required for interaction with betaTrCP.1 Here, we show that phosphorylation at Ser 82 within the DSG motif anchors Cdc25A to betaTrCP and that Chk1-dependent phosphorylation at Ser 76 affects this interaction as well as betaTrCP-dependent degradation. We propose that a hierarchical order of phosphorylation events commits Cdc25A to betaTrCP-dependent degradation. According to our model, phosphorylation at Ser 76 is a "priming" step required for Ser 82 phosphorylation, which in turn allows recruitment of Cdc25A by betaTrCP and subsequent betaTrCP-dependent degradation.

摘要

我们最近证明，在S期以及对DNA损伤作出反应时，Cdc25A蛋白丰度的调节是由SCF(βTrCP)活性介导的。基于已知βTrCP底物的序列同源性，我们发现Cdc25A包含一个保守基序(DSG)，其磷酸化是与βTrCP相互作用所必需的。在此，我们表明DSG基序内Ser 82位点的磷酸化将Cdc25A锚定到βTrCP上，并且Ser 76位点Chk1依赖性磷酸化影响这种相互作用以及βTrCP依赖性降解。我们提出磷酸化事件具有等级顺序，使Cdc25A发生βTrCP依赖性降解。根据我们的模型，Ser 76位点的磷酸化是Ser 82磷酸化所需的“引发”步骤，这反过来又允许βTrCP招募Cdc25A并随后进行βTrCP依赖性降解。