ArticleThe Journal of biological chemistry2004
SH2-B promotes insulin receptor substrate 1 (IRS1)- and IRS2-mediated activation of the phosphatidylinositol 3-kinase pathway in response to leptin.
Article in The Journal of biological chemistry, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 83 papers, 1 of them a synthesis that pooled it.
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Who cites it
83 citing papers in PubMed, 1 synthesis or guideline pooled it, 173 citations in OpenAlex.
- Meta-analyses between 18 candidate genetic markers and overweight/obesity.Diagnostic pathology · 2014Pooled it
- Integrated ATAC-Seq and RNA-Seq Reveal Candidate Regulatory Genes and Chromatin Accessibility Associated with Intramuscular Fat Deposition: An Animal Trial in Hezuo Pigs.Animals : an open access journal from MDPI · 2026Article
- Studies of Foxo1 over the Past 25 Years: Mechanisms of Insulin Resistance and Glucose Dysregulation.Cells · 2026Review
- Review
- Leptin affects spermatogenic function via activation of the Akt/ERK/AMPK signaling pathway.Hormones (Athens, Greece) · 2025Article
- Molecular mechanisms and neural mediators of leptin action.Genes & development · 2025Review
- Identification of βIIΣ1-Spectrin as a Binding Partner of the GH-regulated Human Obesity Scaffold Protein SH2B1.Endocrinology · 2025Article
- Sertoli cells as a hub in testicular development and male reproductive.Frontiers in cell and developmental biology · 2025Review
- KCNB1-Leptin receptor complexes couple electric and endocrine function in the melanocortin neurons of the hypothalamus.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2024Article
- SH2B1 Defends Against Energy Imbalance, Obesity, and Metabolic Disease via a Paraventricular Hypothalamus→Dorsal Raphe Nucleus Neurocircuit.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Molecular insights into Sertoli cell function: how do metabolic disorders in childhood and adolescence affect spermatogonial fate?Nature communications · 2024Review
- Obesity-Associated Breast Cancer: Analysis of Risk Factors and Current Clinical Evaluation.Advances in experimental medicine and biology · 2024Review
- Role of the Beta and Gamma Isoforms of the Adapter Protein SH2B1 in Regulating Energy Balance.Endocrinology · 2023Article
- Detangling the interrelations between MAFLD, insulin resistance, and key hormones.Hormones (Athens, Greece) · 2022Review
- Leptin signaling and leptin resistance.Medical review (2021) · 2022Review
- PTEN Deletion in Adult Mice Induces Hypoinsulinemia With Concomitant Low Glucose Levels.Frontiers in endocrinology · 2022Article
- Differential response to a 6-month energy-restricted treatment depending on SH2B1 rs7359397 variant in NAFLD subjects: Fatty Liver in Obesity (FLiO) Study.European journal of nutrition · 2021Article
- From leptin to lasers: the past and present of mouse models of obesity.Expert opinion on drug discovery · 2021Article
- Interaction of glucose sensing and leptin action in the brain.Molecular metabolism · 2020Review
- Roles of Gangliosides in Hypothalamic Control of Energy Balance: New Insights.International journal of molecular sciences · 2020Review
23 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Leptin regulates energy homeostasis primarily by binding and activating its long form receptor (LRb). Deficiency of either leptin or LRb causes morbid obesity. Leptin stimulates LRb-associated JAK2, thus initiating multiple pathways including the Stat3 and phosphatidylinositol (PI) 3-kinase pathways that mediate leptin biological actions. Here we report that SH2-B, a JAK2-interacting protein, promotes activation of the PI 3-kinase pathway by recruiting insulin receptor substrate 1 (IRS1) and IRS2 in response to leptin. SH2-B directly bound, via its PH and SH2 domain, to both IRS1 and IRS2 both in vitro and in intact cells and mediated formation of a JAK2/SH2-B/IRS1 or IRS2 tertiary complex. Consequently, SH2-B dramatically enhanced leptin-stimulated tyrosine phosphorylation of IRS1 and IRS2 in HEK293 cells stably expressing LRb, thus promoting association of IRS1 and IRS2 with the p85 regulatory subunit of PI 3-kinase and phosphorylation and activation of Akt. SH2-B mutants with lower affinity for IRS1 and IRS2 exhibited reduced ability to promote association of JAK2 with IRS1, tyrosine phosphorylation of IRS1, and association of IRS1 with p85 in response to leptin. Moreover, deletion of the SH2-B gene impaired leptin-stimulated tyrosine phosphorylation of endogenous IRS1 in mouse embryonic fibroblasts (MEF), which was reversed by reintroduction of SH2-B. Similarly, SH2-B promoted growth hormone-stimulated tyrosine phosphorylation of IRS1 in both HEK293 and MEF cells. Our data suggest that SH2-B is a novel mediator of the PI 3-kinase pathway in response to leptin or other hormones and cytokines that activate JAK2.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.