Advances in Biological Regulation
Advances in Biological Regulation
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发表时间：
2020
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通讯作者：
A. R. Ramosa;Somadri Ghosha;Tara Suhela;C. Chevalierb;Eric Owusu Obenga;Bohumil Fafilekd;Pavel Krejcid;Benjamin Becka;Christophe Erneuxa
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作者：
A. R. Ramosa;Somadri Ghosha;Tara Suhela;C. Chevalierb;Eric Owusu Obenga;Bohumil Fafilekd;Pavel Krejcid;Benjamin Becka;Christophe Erneuxa
磷脂酰肌醇（PI）是磷脂酰肌醇的磷酸化衍生物。它们作为信号分子与真核细胞中的基本细胞机制相关，如细胞骨架组织、有丝分裂、极性、迁移或侵袭。PI被大量的PI激酶和PI磷酸酶作用于肌醇环的5-、4-和3-位而磷酸化和去磷酸化。PI 5-磷酸酶即OCRL、INPP 5 B、SHIP 1/2、Synaptojanin 1/2、INPP 5E、INPP 5 J、SKIP（INPP 5 K）是使PI的5-磷酸位置去磷酸化的酶。几种人类遗传性疾病如Lowe综合征、一些先天性肌营养不良和视神经发育不良是由于PI磷酸酶的突变，导致功能丧失。PI磷酸酶在几种人类癌症如胶质母细胞瘤或乳腺癌中也被上调或下调。它们的细胞定位是动态的，并且随着刺激而变化，这是理解功能的重要问题。这是PI 5-磷酸酶SKIP和SHIP 2的两个成员的情况。这两种酶都存在于皱褶、质膜、内质网（SKIP的独特情况）和细胞核中。在定位之后，PI 5磷酸酶作用于PI的特定细胞池，PI继而与靶蛋白相互作用。核PI已成为细胞信号传导不同领域中基因组功能的调节剂。它们通常定位于核斑点，如几种PI代谢激酶和磷酸酶。我们询问SKIP和SHIP 2是否会对核PI（4，5）P2产生影响。在两种胶质母细胞瘤细胞模型中，降低SKIP表达对核PI（4，5）P2有影响。在MCF-7细胞中SHIP 2缺失的模型中，未观察到核PI（4，5）P2的变化。最后，我们提出了SKIP在体内的抗肿瘤作用的证据，在异种移植物中使用作为模型U87 shSKIP细胞。https://doi.org/10.1016/j.jbior.2019.100660 接收日期：2019年8月30日;接收日期：2019年9月18日;接受日期：2019年9月30日缩略语：PI，磷酸肌醇; OPS，视神经发育不良; ER，内质网; PI（4，5）P2，4，5-二磷酸磷脂酰肌醇; GBM，胶质母细胞瘤; FN，纤连蛋白; IPMK，磷酸肌醇多激酶; PI 3 K，磷酸肌醇3-激酶; HBV，B型肝炎病毒; DMEM，Dulbecco改良Eagle培养基; IF，免疫荧光; FCS，胎牛血清; BSA，牛血清白蛋白; NHS，正常马血清; CTCF，校正的总细胞荧光; WT，野生型; PLC，磷脂酶C。IRIBHM，Campus Erasme，Bldg C，808 Route de伦尼克，1070，布鲁塞尔，比利时.电子邮件地址：cerneux@ulb.ac.be（中国）Erneux）。
Phosphoinositides (PIs) are phosphorylated derivatives of phosphatidylinositol. They act as signaling molecules linked to essential cellular mechanisms in eukaryotic cells, such as cytoskeleton organization, mitosis, polarity, migration or invasion. PIs are phosphorylated and dephosphorylated by a large number of PI kinases and PI phosphatases acting at the 5-, 4and 3position of the inositol ring. PI 5-phosphatases i.e. OCRL, INPP5B, SHIP1/2, Synaptojanin 1/2, INPP5E, INPP5J, SKIP (INPP5K) are enzymes that dephosphorylate the 5-phosphate position of PIs. Several human genetic diseases such as the Lowe syndrome, some congenital muscular dystrophy and opsismodysplasia are due to mutations in PI phosphatases, resulting in loss-offunction. The PI phosphatases are also up or down regulated in several human cancers such as glioblastoma or breast cancer. Their cellular localization, that is dynamic and varies in response to stimuli, is an important issue to understand function. This is the case for two members of the PI 5-phosphatase SKIP and SHIP2. Both enzymes are in ruffles, plasma membranes, the endoplasmic reticulum, a situation that is unique for SKIP, and the nucleus. Following localization, PI 5phosphatases act on specific cellular pools of PIs, which in turn interact with target proteins. Nuclear PIs have emerged as regulators of genome functions in different area of cell signaling. They often localize to nuclear speckles, as do several PI metabolizing kinases and phosphatases. We asked whether SKIP and SHIP2 could have an impact on nuclear PI(4,5)P2. In two glioblastoma cell models, lowering SKIP expression had an impact on nuclear PI(4,5)P2. In a model of SHIP2 deletion in MCF-7 cells, no change in nuclear PI(4,5)P2 was observed. Finally, we present evidence of an anti-tumoral role of SKIP in vivo, in xenografts using as model U87shSKIP cells. https://doi.org/10.1016/j.jbior.2019.100660 Received 30 August 2019; Received in revised form 18 September 2019; Accepted 30 September 2019 Abbreviations: PI, phosphoinositide; OPS, opsismodysplasia; ER, endoplasmic reticulum; PI(4,5)P2, phosphatidylinositol 4,5-bisphosphate; GBM, glioblastoma; FN, fibronectin; IPMK, inositol phosphate multikinase; PI3K, phosphoinositide 3-kinase; HBV, hepatitis B virus; DMEM, Dulbecco's modified Eagle's medium; IF, immunofluorescence; FCS, fetal calf serum; BSA, bovine serum albumin; NHS, normal horse serum; CTCF, corrected total cell fluorescence; WT, wild type; PLC, phospholipase C ∗ Corresponding author. IRIBHM, Campus Erasme, Bldg C, 808 Route de Lennik, 1070, Brussels, Belgium. E-mail address: cerneux@ulb.ac.be (C. Erneux).