[Molecular mechanism of SH2B1 in regulating JAK2/IRS2 during obesity development].
OBJECTIVE
In order to investigate the effect of SH2B1 on leptin signal transduction JAK2/IRS2 and its biological function.


METHODS
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.


RESULTS
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.


CONCLUSIONS
SH2B1 is an endogenous enhancer of leptin sensitivity and required for maintaining normal bodyweight in mice via leptin JAK2/IRS2 pathway.
Duan
Chaojun
C
Key Laboratory of Cancer Proteomics, Ministry of Health of China, Xiangya Hospital, Central South University, Changsha 410008, China. duancjxy@126.com
Tang
Can'e
C
Liao
Lan
L
Li
Cui
C
Su
Tao
T
Chen
Zhuchu
Z
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D005260:Female; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism*; D020738:Leptin / Q000097:blood*; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology; D009765:Obesity / Q000209:etiology* / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics* / Q000502:physiology; D054411:Receptors, Leptin / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors
D048868:Adaptor Proteins, Signal Transducing; D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D020738:Leptin; D009687:Nuclear Proteins; D010750:Phosphoproteins; D054411:Receptors, Leptin; C518910:SH2B1 protein, human; C099550:Sh2bp1 protein, mouse; D014157:Transcription Factors; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2