Loijens J C, Boronenkov I V, Parker G J, Anderson R A
Department of Pharmacology, University of Wisconsin Medical School, Madison 53706, USA.
Adv Enzyme Regul. 1996;36:115-40. doi: 10.1016/0065-2571(95)00005-4.
The existence of a PIP5K family of enzymes has been suggested by Western blotting and purification of numerous PIP5Ks from various tissues and cell types. The erythrocyte has at least two PIP5Ks, named PIP5KI and PIP5KII, while the brain appears to have even more isoforms. The cloning of the first PIP5K, the PIP5KII alpha, is just the beginning of the molecular classification of this protein family. The PIP5KII alpha sequence has shown that these enzymes lack obvious homology to protein, sugar and other lipid kinases. The identification of two S. cerevisiae homologues, Mss4p and Fab1p, confirms that this family of kinases is widely distributed in eukaryotes. Not surprisingly, cloning experiments have identified additional isoforms. By cloning additional isoforms, insights into the structure and functions of this family of enzymes will be gained. One reason for a large family of PIP5Ks is that many forms of regulation and cellular functions have been ascribed to PIP5Ks, as summarized in Figure 10. Some of these functional links result from PtdIns[4,5]P2 being required for a given process, but the direct involvement of specific PIP5Ks is not well defined. Which PIP5K isoforms are regulated by a specific mechanism or are involved in a cellular process often is not clear. For example, which PIP5Ks produce PtdIns[4,5]P2 that is hydrolyzed by PLC or phosphorylated by the PI 3-kinase is not known. A few exceptions are PIP5KII not being able to phosphorylate PtdIns[4,5]P2 in native membranes, and PIP5KIs being stimulated by PtdA, required for secretion, and possibly regulated by G proteins of the Rho subfamily. The multiplicity of regulation and functions of each PIP5K isoform remains to be elucidated. Another factor governing the number of isoforms may be presence of multiple pools of polyphosphoinositides and the localizing of PIP5K function within cells. The polyphosphoinositides appear to be compartmentalized within cells and each pool appears to be sensitive to specific signals. These polyphosphoinositide pools may include those in the plasma membrane that are used by PLC, nuclear pools that appear to turn over separately from cytoplasmic pools and a small pool at sites of vesicle fusion with the plasma membrane. Each pool may be controlled by a specific PIP5K isoform. This would explain the diversity of PIP5K cellular roles. Another possibility is that the PIP5Ks are localized to certain areas of the cell by being part of a protein or proteolipid complex. Furthermore, the presence of PITP or PLC in the complex would potentially impart specificity and speed on the use of PtdIns[4]P and PtdIns[4,5]P2 because these lipids could be channeled quickly from one enzyme to the next. The concept of localized complexes containing particular PIP5K isoforms that control the composition of different polyphosphoinositide pools will likely be important as the family of PIP5K isoforms grows.
蛋白质免疫印迹法以及从各种组织和细胞类型中纯化出大量磷脂酰肌醇-4-磷酸5-激酶（PIP5K），提示了PIP5K酶家族的存在。红细胞中至少有两种PIP5K，分别命名为PIP5KI和PIP5KII，而大脑中似乎有更多的同工型。首个PIP5K即PIP5KIIα的克隆，仅仅是这个蛋白质家族分子分类的开端。PIP5KIIα序列表明，这些酶与蛋白质、糖类及其他脂质激酶缺乏明显的同源性。酿酒酵母的两个同源物Mss4p和Fab1p的鉴定，证实了这个激酶家族在真核生物中广泛分布。不出所料，克隆实验鉴定出了其他同工型。通过克隆其他同工型，将有助于深入了解这个酶家族的结构和功能。PIP5K家族庞大的一个原因是，PIP5K具有多种形式的调节作用并参与多种细胞功能，如图10所示。其中一些功能联系源于特定过程需要磷脂酰肌醇-4,5-二磷酸（PtdIns[4,5]P2），但特定PIP5K的直接参与情况尚不明确。哪种PIP5K同工型受特定机制调节或参与某个细胞过程通常并不清楚。例如，哪些PIP5K产生的PtdIns[4,5]P2会被磷脂酶C（PLC）水解或被磷脂酰肌醇-3激酶磷酸化尚不清楚。少数例外情况是，PIP5KII无法在天然膜中磷酸化PtdIns[4,5]P2，而PIP5KIs受分泌所需的磷脂酸（PtdA）刺激，并可能受Rho亚家族的G蛋白调节。每种PIP5K同工型调节和功能的多样性仍有待阐明。决定同工型数量的另一个因素可能是多磷酸肌醇存在多个池以及PIP5K功能在细胞内的定位。多磷酸肌醇似乎在细胞内是分隔存在的，每个池似乎对特定信号敏感。这些多磷酸肌醇池可能包括质膜中被PLC利用的池、似乎与细胞质池分开周转的核池以及小泡与质膜融合部位的一个小池。每个池可能由特定的PIP5K同工型控制。这将解释PIP5K细胞作用的多样性。另一种可能性是，PIP5K通过成为蛋白质或蛋白脂质复合物的一部分而定位于细胞的某些区域。此外，复合物中存在磷脂酰肌醇转运蛋白（PITP）或PLC可能会赋予PtdIns[4]P和PtdIns[4,5]P2使用的特异性和速度，因为这些脂质可以快速从一种酶传递到另一种酶。随着PIP5K同工型家族的发展，包含特定PIP5K同工型以控制不同多磷酸肌醇池组成的局部复合物概念可能会很重要。
