含SH2结构域的肌醇多磷酸5-磷酸酶2：SHIP2

The SH2 domain containing inositol polyphosphate 5-phosphatase-2: SHIP2.

作者信息

Dyson Jennifer M, Kong Anne M, Wiradjaja Fenny, Astle Megan V, Gurung Rajendra, Mitchell Christina A

机构信息

Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton, Vic. 3800, Australia.

出版信息

Int J Biochem Cell Biol. 2005 Nov;37(11):2260-5. doi: 10.1016/j.biocel.2005.05.003.

DOI:10.1016/j.biocel.2005.05.003

PMID:15964236

Abstract

Phosphoinositides are membrane-bound signaling molecules that recruit, activate and localize target effectors to intracellular membranes regulating apoptosis, cell proliferation, insulin signaling and membrane trafficking. The SH2 domain containing inositol polyphosphate 5-phosphatase-2 (SHIP2) hydrolyzes phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) generating phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2). Overexpression of SHIP2 inhibits insulin-stimulated phosphoinositide 3-kinase (PI3K) dependent signaling events. Analysis of diabetic human subjects has revealed an association between SHIP2 gene polymorphisms and type 2 diabetes mellitus. Genetic ablation of SHIP2 in mice has generated conflicting results. SHIP2 knockout mice were originally reported to show lethal neonatal hypoglycemia resulting from insulin hypersensitivity, but in addition to inactivating the SHIP2 gene, the Phox2a gene was also inadvertently deleted. Another SHIP2 knockout mouse has now been generated which inactivates the SHIP2 gene but leaves Phox2a intact. These animals show normal insulin and glucose tolerance but are highly resistant to weight gain on high fat diets, exhibiting an obesity-resistant phenotype. Therefore, SHIP2 remains a significant therapeutic target for the treatment of both obesity and type 2 diabetes.

摘要

磷酸肌醇是膜结合信号分子，可募集、激活靶效应器并将其定位到细胞内膜，从而调节细胞凋亡、细胞增殖、胰岛素信号传导和膜运输。含SH2结构域的肌醇多磷酸5-磷酸酶-2（SHIP2）可水解磷脂酰肌醇3,4,5-三磷酸（PtdIns(3,4,5)P3）生成磷脂酰肌醇3,4-二磷酸（PtdIns(3,4)P2）。SHIP2的过表达会抑制胰岛素刺激的磷酸肌醇3-激酶（PI3K）依赖性信号事件。对糖尿病患者的分析显示，SHIP2基因多态性与2型糖尿病之间存在关联。在小鼠中对SHIP2进行基因敲除产生了相互矛盾的结果。最初报道SHIP2基因敲除小鼠因胰岛素超敏反应而出现致命的新生儿低血糖，但除了使SHIP2基因失活外，Phox2a基因也被意外删除。现在又培育出了另一种SHIP2基因敲除小鼠，它使SHIP2基因失活，但Phox2a基因保持完整。这些动物表现出正常的胰岛素和葡萄糖耐受性，但对高脂饮食引起的体重增加具有高度抗性，呈现出抗肥胖表型。因此，SHIP2仍然是治疗肥胖症和2型糖尿病的重要治疗靶点。