PSM/SH2B1 splice variants: Critical role in src catalytic activation and the resulting STAT3s‐mediated mitogenic response

Zhang, Manchao; Deng, Youping; Riedel, Heimo

doi:10.1002/jcb.21606

Cited by 11 publications

(17 citation statements)

References 71 publications

(98 reference statements)

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“…This indicates that HEK293 cells and the STAT3 assay allow functional characterization of SH2B1. While in mice only the alpha splice variant was tested for leptin signalling [43], we observe an effect on leptin signalling for both other splice variants ( β and γ ) in our human cell system (Figure 2, Additional file 1: Table S2). The analysis of the impact of both SH2B1 variants on leptin receptor activity showed no significant reduction of STAT3 mediated signalling by the risk alleles at rs7498665 and β Thr656Ile/ γ Pro674Ser.…”

Section: Resultsmentioning

confidence: 89%

Mutation screen in the GWAS derived obesity gene SH2B1including functional analyses of detected variants

et al. 2012

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BackgroundThe SH2B1 gene (Src-homology 2B adaptor protein 1 gene) is a solid candidate gene for obesity. Large scale GWAS studies depicted markers in the vicinity of the gene; animal models suggest a potential relevance for human body weight regulation.MethodsWe performed a mutation screen for variants in the SH2B1 coding sequence in 95 extremely obese children and adolescents. Detected variants were genotyped in independent childhood and adult study groups (up to 11,406 obese or overweight individuals and 4,568 controls). Functional implications on STAT3 mediated leptin signalling of the detected variants were analyzed in vitro.ResultsWe identified two new rare mutations and five known SNPs (rs147094247, rs7498665, rs60604881, rs62037368 and rs62037369) in SH2B1. Mutation g.9483C/T leads to a non-synonymous, non-conservative exchange in the beta (βThr656Ile) and gamma (γPro674Ser) splice variants of SH2B1. It was additionally detected in two of 11,206 (extremely) obese or overweight children, adolescents and adults, but not in 4,506 population-based normal-weight or lean controls. The non-coding mutation g.10182C/A at the 3’ end of SH2B1 was only detected in three obese individuals. For the non-synonymous SNP rs7498665 (Thr484Ala) we observed nominal over-transmission of the previously described risk allele in 705 obesity trios (nominal p = 0.009, OR = 1.23) and an increased frequency of the same allele in 359 cases compared to 429 controls (nominal p = 0.042, OR = 1.23). The obesity risk-alleles at Thr484Ala and βThr656Ile/γPro674Ser had no effect on STAT3 mediated leptin receptor signalling in splice variants β and γ.ConclusionThe rare coding mutation βThr656Ile/γPro674Ser (g.9483C/T) in SH2B1 was exclusively detected in overweight or obese individuals. Functional analyzes did not reveal impairments in leptin signalling for the mutated SH2B1.

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Section: Resultsmentioning

confidence: 89%

Mutation screen in the GWAS derived obesity gene SH2B1including functional analyses of detected variants

et al. 2012

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“…A limited number of studies have compared the actions of the various isoforms in vitro. All 4 SH2B1 isoforms enhanced mitogenesis and cell proliferation in response to IGF-I, insulin, and platelet-derived growth factor stimulation (4, 17). Stable expression of each isoform in NIH3T3 fibroblasts led to enhanced insulin receptor autophosphorylation and phosphorylation of IRS1 (17).…”

Section: Discussionmentioning

confidence: 99%

“…All 4 SH2B1 isoforms enhanced mitogenesis and cell proliferation in response to IGF-I, insulin, and platelet-derived growth factor stimulation (4, 17). Stable expression of each isoform in NIH3T3 fibroblasts led to enhanced insulin receptor autophosphorylation and phosphorylation of IRS1 (17). In 3T3-L1 cells, all 4 isoforms enhance insulin-stimulated glucose and amino acid transport, glycogen synthesis, lipogenesis, Akt activity, and p70 S6 kinase activity (18).…”

Section: Discussionmentioning

confidence: 99%

Functional Characterization of Obesity-Associated Variants Involving the α and β Isoforms of Human SH2B1

et al. 2014

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We have previously reported rare variants in sarcoma (Src) homology 2 (SH2) B adaptor protein 1 (SH2B1) in individuals with obesity, insulin resistance, and maladaptive behavior. Here, we identify 4 additional SH2B1 variants by sequencing 500 individuals with severe early-onset obesity. SH2B1 has 4 alternatively spliced isoforms. One variant (T546A) lies within the N-terminal region common to all isoforms. As shown for past variants in this region, T546A impairs SH2B1β enhancement of nerve growth factor-induced neurite outgrowth, and the individual with the T546A variant exhibits mild developmental delay. The other 3 variants (A663V, V695M, and A723V) lie in the C-terminal tail of SH2B1α. SH2B1α variant carriers were hyperinsulinemic but did not exhibit the behavioral phenotype observed in individuals with SH2B1 variants that disrupt all isoforms. In in vitro assays, SH2B1α, like SH2B1β, enhances insulin- and leptin-induced insulin receptor substrate 2 (IRS2) phosphorylation and GH-induced cell motility. None of the variants affect SH2B1α enhancement of insulin- and leptin-induced IRS2 phosphorylation. However, T546A, A663V, and A723V all impair the ability of SH2B1α to enhance GH-induced cell motility. In contrast to SH2B1β, SH2B1α does not enhance nerve growth factor-induced neurite outgrowth. These studies suggest that genetic variants that disrupt isoforms other than SH2B1β may be functionally significant. Further studies are needed to understand the mechanism by which the individual isoforms regulate energy homeostasis and behavior.

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“…Tyr 439 and Tyr 494 are conserved in all four isoforms, and are able to be phosphorylated by JAK1 and JAK2 [23] . Src tyrosine kinases also phosphorylate all four isoforms [24] . Additionally, insulin, insulin-like growth factor (IGF-1), and nerve growth factor (NGF) also stimulate tyrosine phosphorylation of SH2B1 via their cognate receptor tyrosine kinases [14,18,25] .…”

Section: Metabolic Function Of Sh2b1mentioning

confidence: 99%

SH2B1 regulation of energy balance, body weight, and glucose metabolism

Rui

2014

WJD

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The Src homology 2B (SH2B) family members (SH2B1, SH2B2 and SH2B3) are adaptor signaling proteins containing characteristic SH2 and PH domains. SH2B1 (also called SH2-B and PSM) and SH2B2 (also called APS) are able to form homo-or hetero-dimers via their N-terminal dimerization domains. Their C-terminal SH2 domains bind to tyrosyl phosphorylated proteins, including Janus kinase 2 (JAK2), TrkA, insulin receptors, insulin-like growth factor-1 receptors, insulin receptor substrate-1 (IRS1), and IRS2. SH2B1 enhances leptin signaling by both stimulating JAK2 activity and assembling a JAK2/ IRS1/2 signaling complex. SH2B1 promotes insulin signaling by both enhancing insulin receptor catalytic activity and protecting against dephosphorylation of IRS proteins. Accordingly, genetic deletion of SH2B1 results in severe leptin resistance, insulin resistance, hyperphagia, obesity, and type 2 diabetes in mice. Neuronspecific overexpression of SH2B1β transgenes protects against diet-induced obesity and insulin resistance. SH2B1 in pancreatic β cells promotes β cell expansion and insulin secretion to counteract insulin resistance in obesity. Moreover, numerous SH2B1 mutations are genetically linked to leptin resistance, insulin resistance, obesity, and type 2 diabetes in humans. Unlike SH2B1, SH2B2 and SH2B3 are not required for the maintenance of normal energy and glucose homeostasis. The metabolic function of the SH2B family is conserved from insects to humans. Key words: Obesity; Type 2 diabetes; Leptin resistance; Insulin resistance; Glucose intolerance; Hypothalamus; Energy balance; Food intake; Hyperphagia; Nonalcoholic fatty liver disease Core tip: The Src homology 2B (SH2B) family members mediate cell signaling in response to a variety of hormones, cytokines, and growth factors. In the brain, SH2B1 enhances leptin signaling and leptin's antiobesity action. In peripheral tissues, SH2B1 cell-autonomously enhances insulin signaling. In pancreatic islets, SH2B1 is required for compensatory β cell expansion in response to insulin resistance and β cell stress. SH2B1-deficiency results in severe leptin resistance, energy imbalance, obesity, and type 2 diabetes. SH2B1 mutations are linked to leptin resistance, insulin resistance, obesity, and type 2 diabetes in humans. Thus, SH2B1 is a critical metabolic regulator in mammals.Rui L. SH2B1 regulation of energy balance, body weight, and glucose metabolism. World J Diabetes 2014; 5(4): 511-526 Available from:

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PSM/SH2B1 splice variants: Critical role in src catalytic activation and the resulting STAT3s‐mediated mitogenic response

Cited by 11 publications

References 71 publications

Mutation screen in the GWAS derived obesity gene SH2B1including functional analyses of detected variants

Mutation screen in the GWAS derived obesity gene SH2B1including functional analyses of detected variants

Functional Characterization of Obesity-Associated Variants Involving the α and β Isoforms of Human SH2B1

SH2B1 regulation of energy balance, body weight, and glucose metabolism

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