{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, the Src homology 2‑B adaptor protein 1 (SH2B1) functions as a critical intracellular scaffold that binds to activated receptor tyrosine kinases. Its SH2 domain mediates association with kinases such as Janus kinase 2 (JAK2) and the RET receptor, thereby enhancing receptor autophosphorylation and downstream signaling initiated by ligands including leptin, insulin, growth hormone, and nerve growth factor. Moreover, studies of its alternatively spliced isoforms reveal that SH2B1 can homodimerize via a unique N‑terminal region and depends on functionally important domains such as the pleckstrin homology region for proper intracellular targeting and signaling modulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFunctional studies in both humans and mice have consistently shown that disruption of SH2B1 signaling predisposes to metabolic dysregulation. Genome‐wide association studies and targeted mutation analyses have linked variants in or near SH2B1 to increased body mass index, hyperphagia, altered adipose tissue distribution, insulin resistance, and even neurobehavioral abnormalities. In murine models, loss‐of‐function or deletion of Sh2b1 in key hypothalamic neurons diminishes leptin-induced activation of sympathetic outflow and brown adipose tissue thermogenesis, while human mutation carriers often exhibit severe early-onset obesity and maladaptive behavior."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in metabolic homeostasis, SH2B1 also contributes to cellular dynamics. It enhances growth hormone- and insulin-mediated responses by modulating receptor signaling cascades that impact actin cytoskeletal remodeling and cell motility—effects observed in processes like neurite outgrowth and even cardiac hypertrophy. Furthermore, distinct rare variants in SH2B1 can differentially impair its ability to promote growth factor–induced cell movement, and deregulation of SH2B1 expression (for example, via competing endogenous RNA networks) has been implicated in promoting malignant progression in colorectal cancer. These findings underscore the multifunctional role of SH2B1 in both metabolic regulation and cytoskeletal control."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Masahiro Nishi, Eric D Werner, Byung-Chul Oh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Kinase activation through dimerization by human SH2-B."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.25.7.2607-2621.2005"}], "href": "https://doi.org/10.1128/MCB.25.7.2607-2621.2005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15767667"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15767667"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Yalda Jamshidi, Harold Snieder, Dongliang Ge, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "SH2B1beta adaptor is a key enhancer of RET tyrosine kinase signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1210480"}], "href": "https://doi.org/10.1038/sj.onc.1210480"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17471236"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17471236"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Gudmar Thorleifsson, G Bragi Walters, Daniel F Gudbjartsson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.274"}], "href": "https://doi.org/10.1038/ng.274"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19079260"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19079260"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Cristen J Willer, Elizabeth K Speliotes, Ruth J F Loos, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Six new loci associated with body mass index highlight a neuronal influence on body weight regulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.287"}], "href": "https://doi.org/10.1038/ng.287"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19079261"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19079261"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Frida Renström, Felicity Payne, Anna Nordström, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Replication and extension of genome-wide association study results for obesity in 4923 adults from northern Sweden."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddp041"}], "href": "https://doi.org/10.1093/hmg/ddp041"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19164386"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19164386"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Ruxandra Bachmann-Gagescu, Heather C Mefford, Charles Cowan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Recurrent 200-kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genet Med (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/GIM.0b013e3181ef4286"}], "href": "https://doi.org/10.1097/GIM.0b013e3181ef4286"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20808231"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20808231"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Bo Xi, Yue Shen, Kathleen Heather Reilly, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sex-dependent associations of genetic variants identified by GWAS with indices of adiposity and obesity risk in a Chinese children population."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Endocrinol (Oxf) (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cen.12091"}], "href": "https://doi.org/10.1111/cen.12091"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23121087"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23121087"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Leah Rider, Maria Diakonova "}, {"type": "b", "children": [{"type": "t", "text": "Adapter protein SH2B1beta binds filamin A to regulate prolactin-dependent cytoskeletal reorganization and cell motility."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Endocrinol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/me.2011-0056"}], "href": "https://doi.org/10.1210/me.2011-0056"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21566085"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21566085"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Laura R Pearce, Ray Joe, Michael E Doche, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Functional characterization of obesity-associated variants involving the α and β isoforms of human SH2B1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocrinology (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/en.2014-1264"}], "href": "https://doi.org/10.1210/en.2014-1264"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24971614"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24971614"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Gang Wu, Yu Liu, He Huang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SH2B1 is critical for the regulation of cardiac remodelling in response to pressure overload."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cardiovasc Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/cvr/cvv170"}], "href": "https://doi.org/10.1093/cvr/cvv170"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26077624"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26077624"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Canhui Jin, Aihong Wang, Linbo Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hsa_circ_0136666 promotes the proliferation and invasion of colorectal cancer through miR-136/SH2B1 axis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Physiol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcp.27482"}], "href": "https://doi.org/10.1002/jcp.27482"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30370521"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30370521"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Anabel Flores, Lawrence S Argetsinger, Lukas K J Stadler, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Crucial Role of the SH2B1 PH Domain for the Control of Energy Balance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetes (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2337/db19-0608"}], "href": "https://doi.org/10.2337/db19-0608"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31439647"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31439647"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Lin Jiang, Haoran Su, Xiaoyin Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Leptin receptor-expressing neuron Sh2b1 supports sympathetic nervous system and protects against obesity and metabolic disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-020-15328-3"}], "href": "https://doi.org/10.1038/s41467-020-15328-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32251290"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32251290"}]}]}]}