SH2B regulation of growth, metabolism, and longevity in both insects and mammals.
SH2B1 is a key regulator of body weight in mammals. Here, we identified dSH2B as the Drosophila homolog of SH2B1. dSH2B bound to Chico and directly promoted insulin-like signaling. Disruption of dSH2B decreased insulin-like signaling and somatic growth in flies. dSH2B deficiency also increased hemolymph carbohydrate levels, whole-body lipid levels, life span, and resistance to starvation and oxidative stress. Systemic overexpression of dSH2B resulted in opposite phenotypes. dSH2B overexpression in fat body decreased lipid and glucose levels, whereas neuron-specific overexpression of dSH2B decreased oxidative resistance and life span. Genetic deletion of SH2B1 also resulted in growth retardation, obesity, and type 2 diabetes in mice; surprisingly, life span and oxidative resistance were reduced in SH2B1 null mice. These data suggest that dSH2B regulation of insulin-like signaling, growth, and metabolism is conserved in SH2B1, whereas dSH2B regulation of oxidative stress and longevity may be conserved in other SH2B family members.
Song
Wei
W
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Ren
Decheng
D
Li
Wenjun
W
Jiang
Lin
L
Cho
Kae Won
KW
Huang
Ping
P
Fan
Chen
C
Song
Yiyun
Y
Liu
Yong
Y
Rui
Liangyou
L
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000375:Aging; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology; D004330:Drosophila / Q000254:growth & development / Q000378:metabolism; D029721:Drosophila Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D050356:Lipid Metabolism; D008136:Longevity; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology; D018384:Oxidative Stress; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D029721:Drosophila Proteins; C544453:Lnk protein, Drosophila; C115327:Sh2bpsm1 protein, mouse; D005947:Glucose