Ooms Lisa M, Horan Kristy A, Rahman Parvin, Seaton Gillian, Gurung Rajendra, Kethesparan Dharini S, Mitchell Christina A
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
Biochem J. 2009 Apr 1;419(1):29-49. doi: 10.1042/BJ20081673.
Phosphoinositides are membrane-bound signalling molecules that regulate cell proliferation and survival, cytoskeletal reorganization and vesicular trafficking by recruiting effector proteins to cellular membranes. Growth factor or insulin stimulation induces a canonical cascade resulting in the transient phosphorylation of PtdIns(4,5)P(2) by PI3K (phosphoinositide 3-kinase) to form PtdIns(3,4,5)P(3), which is rapidly dephosphorylated either by PTEN (phosphatase and tensin homologue deleted on chromosome 10) back to PtdIns(4,5)P(2), or by the 5-ptases (inositol polyphosphate 5-phosphatases), generating PtdIns(3,4)P(2). The 5-ptases also hydrolyse PtdIns(4,5)P(2), forming PtdIns4P. Ten mammalian 5-ptases have been identified, which share a catalytic mechanism similar to that of the apurinic/apyrimidinic endonucleases. Gene-targeted deletion of 5-ptases in mice has revealed that these enzymes regulate haemopoietic cell proliferation, synaptic vesicle recycling, insulin signalling, endocytosis, vesicular trafficking and actin polymerization. Several studies have revealed that the molecular basis of Lowe's syndrome is due to mutations in the 5-ptase OCRL (oculocerebrorenal syndrome of Lowe). Futhermore, the 5-ptases SHIP [SH2 (Src homology 2)-domain-containing inositol phosphatase] 2, SKIP (skeletal muscle- and kidney-enriched inositol phosphatase) and 72-5ptase (72 kDa 5-ptase)/Type IV/Inpp5e (inositol polyphosphate 5-phosphatase E) are implicated in negatively regulating insulin signalling and glucose homoeostasis in specific tissues. SHIP2 polymorphisms are associated with a predisposition to insulin resistance. Gene profiling studies have identified changes in the expression of various 5-ptases in specific cancers. In addition, 5-ptases such as SHIP1, SHIP2 and 72-5ptase/Type IV/Inpp5e regulate macrophage phagocytosis, and SHIP1 also controls haemopoietic cell proliferation. Therefore the 5-ptases are a significant family of signal-modulating enzymes that govern a plethora of cellular functions by regulating the levels of specific phosphoinositides. Emerging studies have implicated their loss or gain of function in human disease.
磷酸肌醇是膜结合信号分子，通过将效应蛋白招募到细胞膜来调节细胞增殖与存活、细胞骨架重组和囊泡运输。生长因子或胰岛素刺激诱导一个经典级联反应，导致PI3K（磷脂酰肌醇3激酶）将PtdIns(4,5)P(2)短暂磷酸化形成PtdIns(3,4,5)P(3)，其可被PTEN（第10号染色体缺失的磷酸酶和张力蛋白同源物）迅速去磷酸化变回PtdIns(4,5)P(2)，或被5-磷酸酶（肌醇多磷酸5-磷酸酶）作用，生成PtdIns(3,4)P(2)。5-磷酸酶也水解PtdIns(4,5)P(2)，形成PtdIns4P。已鉴定出10种哺乳动物5-磷酸酶，它们具有与脱嘌呤/脱嘧啶核酸内切酶相似的催化机制。在小鼠中对5-磷酸酶进行基因靶向缺失研究表明，这些酶调节造血细胞增殖、突触囊泡循环、胰岛素信号传导、内吞作用、囊泡运输和肌动蛋白聚合。多项研究表明，Lowe综合征的分子基础是5-磷酸酶OCRL（Lowe眼脑肾综合征）发生突变。此外，5-磷酸酶SHIP [含SH2（Src同源2）结构域的肌醇磷酸酶] 2、SKIP（骨骼肌和肾脏富集的肌醇磷酸酶）和72-5磷酸酶（72 kDa 5-磷酸酶）/IV型/Inpp5e（肌醇多磷酸5-磷酸酶E）参与在特定组织中负向调节胰岛素信号传导和葡萄糖稳态。SHIP2基因多态性与胰岛素抵抗易感性相关。基因谱研究已确定特定癌症中各种5-磷酸酶的表达变化。此外，SHIP1、SHIP2和72-5磷酸酶/IV型/Inpp5e等5-磷酸酶调节巨噬细胞吞噬作用，SHIP1还控制造血细胞增殖。因此，5-磷酸酶是一类重要的信号调节酶家族，通过调节特定磷酸肌醇的水平来控制大量细胞功能。新出现的研究表明它们的功能丧失或获得与人类疾病有关。
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