PIP4Kβ interacts with and modulates nuclear localization of the high-activity PtdIns5P-4-kinase isoform PIP4Kα
PIP4Kβ interacts with and modulates nuclear localization of the high-activity PtdIns5P-4-kinase isoform PIP4Kα
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DOI：
10.1042/bj20100341
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发表时间：
2010-09-01
影响因子：
4.1
通讯作者：
Divecha, Nullin
中科院分区：
文献类型：
--
作者：
Bultsma, Yvette;Keune, Willem-Jan;Divecha, Nullin
PIP4K的β -异构体（PtdIns5P-4激酶）调节核PtdIns5P的水平，进而调节肿瘤抑制因子p53的乙酰化。PIP4K β的晶体结构表明，两个亚基的排列方向相反，可以形成同型二聚体。通过质谱、PIP4Ks亚型特异性抗体、RNAi （RNA干扰）抑制和过表达研究，我们发现PIP4K β在体外和体内与P1P4K α亚型相互作用。由于这两种异构体磷酸化相同的底物以产生相同的产物，这种相互作用可以被认为是功能冗余的。然而，与预期相反，我们发现PIP4K beta对PtdIns5P的活性比PIP4K alpha低2000倍，并且与P1P4K beta相关的大部分PIP4K活性来自其与PIP4K alpha的相互作用。此外，PIP4K β可以调节PIP4K α的核定位，PIP4K α具有调节PIP4K β功能的作用。本研究的结果提出了PIP4K α和PIP4K β之间功能相互作用的基本原理，并提供了两种酶的相对水平如何在其生理和病理作用中发挥重要作用的见解。
The beta-isoform of PIP4K (PtdIns5P-4-kinase) regulates the levels of nuclear PtdIns5P, which in turn modulates the acetylation of the tumour suppressor p53. The crystal structure of PIP4K beta demonstrated that it can form a homodimer with the two subunits arranged in opposite orientations. Using MS, isoform-specific antibodies against PIP4Ks, RNAi (RNA interference) suppression and overexpression studies, we show that PIP4K beta interacts in vitro and in vivo with the P1P4K alpha isoform. As the two isoforrns phosphorylate the same substrate to generate the same product, the interaction could be considered to be functionally redundant. However, contrary to expectation, we find that PIP4K beta has 2000-fold less activity towards PtdIns5P compared with PIP4K alpha, and that the majority of PIP4K activity associated with P1P4K beta comes from its interaction with PIP4K alpha. Furthermore, PIP4K beta can modulate the nuclear localization of PIP4K alpha, and PIP4K alpha has a role in regulating PIP4K beta functions. The results of the present study suggest a rationale for the functional interaction between PIP4K alpha and PIP4K beta and provide insight into how the relative levels of the two enzymes may be important in their physiological and pathological roles.