Dyson Jennifer M, Fedele Clare G, Davies Elizabeth M, Becanovic Jelena, Mitchell Christina A
Department of Biochemistry and Molecular Biology, Monash University, Wellington Rd, 3800, Clayton, Australia.
Subcell Biochem. 2012;58:215-79. doi: 10.1007/978-94-007-3012-0_7.
Phosphoinositide phosphatases comprise several large enzyme families with over 35 mammalian enzymes identified to date that degrade many phosphoinositide signals. Growth factor or insulin stimulation activates the phosphoinositide 3-kinase that phosphorylates phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P(2)] to form phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P(3)], which is rapidly dephosphorylated either by PTEN (phosphatase and tensin homologue deleted on chromosome 10) to PtdIns(4,5)P(2), or by the 5-phosphatases (inositol polyphosphate 5-phosphatases), generating PtdIns(3,4)P(2). 5-phosphatases also hydrolyze PtdIns(4,5)P(2) forming PtdIns(4)P. Ten mammalian 5-phosphatases have been identified, which regulate hematopoietic cell proliferation, synaptic vesicle recycling, insulin signaling, and embryonic development. Two 5-phosphatase genes, OCRL and INPP5E are mutated in Lowe and Joubert syndrome respectively. SHIP [SH2 (Src homology 2)-domain inositol phosphatase] 2, and SKIP (skeletal muscle- and kidney-enriched inositol phosphatase) negatively regulate insulin signaling and glucose homeostasis. SHIP2 polymorphisms are associated with a predisposition to insulin resistance. SHIP1 controls hematopoietic cell proliferation and is mutated in some leukemias. The inositol polyphosphate 4-phosphatases, INPP4A and INPP4B degrade PtdIns(3,4)P(2) to PtdIns(3)P and regulate neuroexcitatory cell death, or act as a tumor suppressor in breast cancer respectively. The Sac phosphatases degrade multiple phosphoinositides, such as PtdIns(3)P, PtdIns(4)P, PtdIns(5)P and PtdIns(3,5)P(2) to form PtdIns. Mutation in the Sac phosphatase gene, FIG4, leads to a degenerative neuropathy. Therefore the phosphatases, like the lipid kinases, play major roles in regulating cellular functions and their mutation or altered expression leads to many human diseases.
磷酸肌醇磷酸酶包含几个大的酶家族，迄今为止已鉴定出超过35种哺乳动物酶，它们可降解多种磷酸肌醇信号。生长因子或胰岛素刺激可激活磷酸肌醇3激酶，该激酶将磷脂酰肌醇（4,5）-二磷酸[PtdIns(4,5)P(2)]磷酸化，形成磷脂酰肌醇（3,4,5）-三磷酸[PtdIns(3,4,5)P(3)]，其可通过PTEN（第10号染色体缺失的磷酸酶和张力蛋白同源物）迅速去磷酸化形成PtdIns(4,5)P(2)，或通过5-磷酸酶（肌醇多磷酸5-磷酸酶）生成PtdIns(3,4)P(2)。5-磷酸酶还可水解PtdIns(4,5)P(2)形成PtdIns(4)P。已鉴定出10种哺乳动物5-磷酸酶，它们调节造血细胞增殖、突触小泡循环、胰岛素信号传导和胚胎发育。两种5-磷酸酶基因OCRL和INPP5E分别在洛氏综合征和乔伯特综合征中发生突变。SHIP [SH2（Src同源2）结构域肌醇磷酸酶] 2和SKIP（骨骼肌和肾脏富集的肌醇磷酸酶）对胰岛素信号传导和葡萄糖稳态起负调节作用。SHIP2多态性与胰岛素抵抗易感性相关。SHIP1控制造血细胞增殖，在某些白血病中发生突变。肌醇多磷酸4-磷酸酶INPP4A和INPP4B分别将PtdIns(3,4)P(2)降解为PtdIns(3)P，并调节神经兴奋性细胞死亡，或在乳腺癌中作为肿瘤抑制因子发挥作用。Sac磷酸酶可降解多种磷酸肌醇，如PtdIns(3)P、PtdIns(4)P、PtdIns(5)P和PtdIns(3,5)P(2)，形成PtdIns。Sac磷酸酶基因FIG4发生突变会导致一种退行性神经病变。因此，磷酸酶与脂质激酶一样，在调节细胞功能中起主要作用，其突变或表达改变会导致许多人类疾病。
