Disruption of the <i>SH2</i>-<i>B</i> Gene Causes Age-Dependent Insulin Resistance and Glucose Intolerance

Duan, Chaojun; Yang, Hongyan; White, Morris F.; Rui, Liangyou

doi:10.1128/mcb.24.17.7435-7443.2004

Cited by 117 publications

(123 citation statements)

References 53 publications

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“…SH2B1 is a widely-expressed cytoplasmic protein that simultaneously binds, via its Src homology 2 (SH2) domain, to both Janus kinase 2 (JAK2) and insulin receptor substrate 2 (IRS2), thereby promoting the leptin-induced activation of the phosphoinositide 3-kinase signaling pathway in cultured cells (25,26). SH2B1-deficient mice develop insulin resistance and type 2 diabetes mellitus (27) as well as severe leptin resistance, hyperphagia and obesity (28). SH2B1 is thus a key cytoplasmic signaling molecule that acts as a positive regulator of leptin and insulin signal transduction in mice.…”

Section: Discussionmentioning

confidence: 99%

Association of genetic variants of MAOA and SH2B1 with bone mineral density in community-dwelling Japanese women

Yamada

Ando²,

Shimokata³

2008

Mol Med Report

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Abstract. Although bone mineral density (BMD) is a complex trait that is influenced by both genetic and environmental factors, heritability studies in twins and families have shown that genetic factors account for 60-85% of its variance. We examined the relation of the variable number of tandem repeats (VNTR) polymorphism of the monoamine oxidase A gene (MAOA) and the A'G (Thr484Ala) polymorphism of the SH2B adaptor protein 1 gene (SH2B1) to BMD in communitydwelling Japanese women and men. The 2235 subjects (1107 women, 1128 men) were aged 40-79 years and were randomly recruited for a population-based prospective cohort study of aging and age-related diseases in Japan. BMD at the distal and proximal radius was measured by peripheral quantitative computed tomography, and the BMD of the total body, lumbar spine (L2-L4), right femoral neck and right trochanter was measured by dual-energy X-ray absorptiometry. The genotypes of the VNTR polymorphism of MAOA were determined by DNA fragment analysis, and those of the A'G (Thr484Ala) polymorphism of SH2B1 by melting curve analysis. The VNTR polymorphism of MAOA was associated with the BMD of the distal radius, total body, lumbar spine and trochanter in all women, and with the BMD of the total body and trochanter in postmenopausal ones, with the L (four repeats) and S (two or three repeats) alleles reflecting increased and decreased BMD, respectively. The A'G (Thr484Ala) polymorphism of SH2B1 was associated with the BMD of the lumbar spine in all women, with the BMD of the proximal radius in premenopausal women and with the BMD of the lumbar spine, femoral neck and trochanter in postmenopausal women, with the variant G allele being related to increased BMD. These results suggest that MAOA and SH2B1 are determinative loci for bone mass in Japanese women, especially in postmenopausal ones.

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Section: Discussionmentioning

confidence: 99%

Association of genetic variants of MAOA and SH2B1 with bone mineral density in community-dwelling Japanese women

Yamada

Ando²,

Shimokata³

2008

Mol Med Report

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“…4). 28) This gene has recently been reported to be expressed at accelerated leaves in monocytes and lymphocytes in NIDDM patients after onset. 29) This report supports our hypothesis that the expression of NIDDMrelated genes is altered in blood cells before onset.…”

Section: Fig 4 Schematic Representation Of Niddm Related Signals Inmentioning

confidence: 99%

Genome Wide Expression Analysis of White Blood Cells and Liver of Pre-diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) Rats Using a cDNA Microarray

Iida

Sato

Nakaya

et al. 2006

Biological & Pharmaceutical Bulletin

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In a prior study, we reported on a significant decrease in calpain10 gene expression in white blood cells (WBC) as well as the major insulin-target tissues including liver and adipose tissue, before the onset of diabetes in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. In this study, we extended our hypothesis that some type 2 diabetes mellitus (NIDDM) susceptible genes are up/down-regulated before the onset in WBC of OLETF rats, reflecting their up/down-regulation in major insulin-target tissues, such as the liver. We tested this hypothesis using rat cDNA microarrays. The findings show that 1080 genes are up/down-regulated by more than 2-fold compared to the controls, Long-Evans Tokushima Otsuka rats, before the onset in WBC and liver under fasted or insulin administered condition. Fifty-seven of the 1080 genes were up/down-regulated in both WBC and the liver. More than half have been reported to NIDDM susceptible genes and the remainder have not been reported to be related to NIDDM. These results indicate that there some NIDDM related genes are up/down-regulated in WBC before the onset of diabetes.

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“…SH2B1 -/-mice exhibit a variety of phenotypes (Duan et al, 2004b;Ohtsuka et al, 2002;Ren et al, 2005), including obesity and insulin-resistance, consistent with SH2B1 serving as an adapter or scaffold protein for leptin and insulin (Duan et al, 2004b;Ren et al, 2005). SH2B1 was recently identified as a candidate human obesity gene in genetic studies of patients exhibiting severe early-onset childhood obesity, developmental delay and insulin resistance (Bochukova et al, 2010;Renstrom et al, 2009;Walters et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation controls a dual-function polybasic nuclear localization sequence in the adapter protein SH2B1β to regulate its cellular function and distribution

Maures

Argetsinger

et al. 2011

Journal of Cell Science

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SummaryAn intriguing question in cell biology is what targets proteins to, and regulates their translocation between, specific cellular locations. Here we report that the polybasic nuclear localization sequence (NLS) required for nuclear entry of the adapter protein and candidate human obesity gene product SH2B1b, also localizes SH2B1b to the plasma membrane (PM), most probably via electrostatic interactions. Binding of SH2B1b to the PM also requires its dimerization domain. Phosphorylation of serine residues near this polybasic region, potentially by protein kinase C, releases SH2B1b from the PM and enhances nuclear entry. Release of SH2B1b from the PM and/or nuclear entry appear to be required for SH2B1b enhancement of nerve growth factor (NGF)-induced expression of urokinase plasminogen activator receptor gene and neurite outgrowth of PC12 cells. Taken together, our results provide strong evidence that the polybasic NLS region of SH2B1 serves the dual function of localizing SH2B1 to both the nucleus and the PM, the latter most probably through electrostatic interactions that are enhanced by SH2B1b dimerization. Cycling between the different cellular compartments is a consequence of the phosphorylation and dephosphorylation of serine residues near the NLS and is important for physiological effects of SH2B1, including NGF-induced gene expression and neurite outgrowth.

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Disruption of the SH2-B Gene Causes Age-Dependent Insulin Resistance and Glucose Intolerance

Cited by 117 publications

References 53 publications

Association of genetic variants of MAOA and SH2B1 with bone mineral density in community-dwelling Japanese women

Association of genetic variants of MAOA and SH2B1 with bone mineral density in community-dwelling Japanese women

Genome Wide Expression Analysis of White Blood Cells and Liver of Pre-diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) Rats Using a cDNA Microarray

Phosphorylation controls a dual-function polybasic nuclear localization sequence in the adapter protein SH2B1β to regulate its cellular function and distribution

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