Impact of Src homology 2-containing inositol 5′-phosphatase 2 gene polymorphisms detected in a Japanese population on insulin signaling
Impact of Src homology 2-containing inositol 5′-phosphatase 2 gene polymorphisms detected in a Japanese population on insulin signaling
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DOI：
10.1210/jc.2004-1724
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发表时间：
2005-05-01
影响因子：
5.8
通讯作者：
Kobayashi, M
中科院分区：
文献类型：
--
作者：
Kagawa, S;Sasaoka, T;Kobayashi, M
含Src同源2的5 ′-肌醇磷酸酶2（SHIP 2）是一种脂质磷酸酶，它能将PI（3，4，5）P-3转化为PI（3，4）P-2，参与胰岛素信号转导的负调控，对胰岛素抵抗状态有重要影响。为了阐明SHIP 2可能参与人类2型糖尿病的发病机制，我们研究了日本人群中SHIP 2基因多态性与2型糖尿病的关系。我们确定了10个多态性，包括4个错义突变。其中，单核苷酸多态性（SNP）3（L 632 I）位于5 ′-磷酸酶催化区，SNP 5（N982 S）位于C端磷酸酪氨酸结合域结合共有基序附近。SNP 3在对照组中比在2型糖尿病患者中更常见，这表明该突变可能保护胰岛素抵抗。转染实验表明，SNP 3-SHIP 2表达对胰岛素诱导的PI（3，4，5）P-3产生和Akt 2磷酸化的抑制作用弱于野生型SHIP 2表达。与野生型SHIP 2相比，胰岛素诱导的SNP 5-SHIP 2的酪氨酸磷酸化降低，导致Shc/Grb 2结合和MAPK激活增加。这些结果表明，SHIP 2的多态性至少部分地与2型糖尿病有关，可能是通过影响日本人群中的代谢和/或促有丝分裂胰岛素信号传导。
Src homology 2-containing 5'-inositol phosphatase 2 (SHIP2) is known to be one of lipid phosphatases converting PI(3,4,5) P-3 to PI(3,4) P-2 in the negative regulation of insulin signaling with the fundamental impact on the state of insulin resistance. To clarify the possible involvement of SHIP2 in the pathogenesis of human type 2 diabetes, we examined the relation of human SHIP2 gene polymorphisms to type 2 diabetes in a Japanese population. We identified 10 polymorphisms including four missense mutations. Among them, single nucleotide polymorphism ( SNP) 3 (L632I) was located in the 5'-phosphatase catalytic region, and SNP5 (N982S) was adjacent to the phosphotyrosine binding domain binding consensus motif in the C terminus. SNP3 was found more frequently in control subjects than in type 2 diabetic patients, suggesting that this mutation might protect from insulin resistance. Transfection study showed that expression of SNP3-SHIP2 inhibited insulin-induced PI( 3,4,5) P-3 production and Akt2 phosphorylation less potently than expression of wild-type SHIP2 in CHO-IR cells. Insulin-induced tyrosine phosphorylation of SNP5-SHIP2 was decreased compared with that of wild-type SHIP2, resulting in increased Shc/Grb2 association and MAPK activation. These results indicate that the polymorphisms of SHIP2 are implicated, at least in part, in type 2 diabetes, possibly by affecting the metabolic and/or mitogenic insulin signaling in the Japanese population.