Duan Chaojun, Tang Can'e, Liao Lan, Li Cui, Su Tao, Chen Zhuchu
Key Laboratory of Cancer Proteomics, Ministry of Health of China, Xiangya Hospital, Central South University, Changsha 410008, China.
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2010 Mar;35(3):209-14. doi: 10.3969/j.issn.1672-7347.2010.03.004.
In order to investigate the effect of SH2B1 on leptin signal transduction JAK2/IRS2 and its biological function.
Vitro kinase assay and Western blot were used to analyse tyrosine phosphorylatin of key molecule JAK2 and insulin receptor substrate-2 (IRS2). ELISA was used to measure the plasma leptin levels in mice. The postnatal growth of mice was monitored over 27 weeks.
SH2B1 dramatically enhanced the leptin-stimulated tyrosine phosphorylation of JAK2 and IRS2 in HEK293 cells stably expressing LRb (HEK239(LRb)). Leptin-stimulated activation of hypothalamic JAK2 and phosphorylation of hyphothalamic IRS2 were significantly impaired in SH2B1(-/-) mice. The deletion of SH2B1 led to leptin resistance,and fasting and randomly fed plasma leptin levels were respectively 3.2 times and 5.1 times higher in SH2B1(-/-) males than wild-type littermates at 15 weeks of age. SH2B1(-/-) males gained body weight rapidly and exceeded wild-type littermates from 5th week. SH2B1(-/-) (at 21 weeks) was approximately twice heavier than wild-type littermates.
SH2B1 is an endogenous enhancer of leptin sensitivity and required for maintaining normal bodyweight in mice via leptin JAK2/IRS2 pathway.
研究SH2B1对瘦素信号转导JAK2/IRS2的影响及其生物学功能。
采用体外激酶分析和蛋白质印迹法分析关键分子JAK2和胰岛素受体底物-2（IRS2）的酪氨酸磷酸化。采用酶联免疫吸附测定法检测小鼠血浆瘦素水平。对小鼠出生后的生长情况进行了27周的监测。
在稳定表达LRb的HEK293细胞（HEK239(LRb)）中，SH2B1显著增强了瘦素刺激的JAK2和IRS2的酪氨酸磷酸化。在SH2B1基因敲除小鼠中，瘦素刺激的下丘脑JAK2激活和下丘脑IRS2磷酸化明显受损。SH2B1的缺失导致瘦素抵抗，15周龄时，SH2B1基因敲除雄性小鼠的空腹和随机进食血浆瘦素水平分别比野生型同窝小鼠高3.2倍和5.1倍。SH2B1基因敲除雄性小鼠体重迅速增加，从第5周开始超过野生型同窝小鼠。SH2B1基因敲除小鼠（21周龄）的体重约为野生型同窝小鼠的两倍。
SH2B1是瘦素敏感性的内源性增强剂，通过瘦素JAK2/IRS2途径维持小鼠正常体重。
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