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[摘要]：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. |
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