# SH2B1

## Overview
The SH2B1 gene encodes the SH2B adaptor protein 1, a multifunctional adapter protein that plays a pivotal role in various cellular signaling pathways. This protein is characterized by its SH2 (Src Homology 2) domain, which facilitates interactions with phosphorylated tyrosine residues, and a pleckstrin homology (PH) domain that aids in membrane association (Aerts2015Genetic; McKercher2017Diversity). SH2B1 is integral to insulin and leptin signaling, enhancing insulin receptor activity and promoting energy balance and body weight regulation through its interactions with JAK2 and IRS proteins (Rui2014SH2B1; Morris2009SH2B1). Additionally, SH2B1 is involved in neuronal differentiation, suggesting a role in neurodevelopment (Hsu2014Signaling). Clinically, mutations in SH2B1 are associated with obesity, insulin resistance, and developmental disorders, underscoring its significance in metabolic and developmental health (BachmannGagescu2010Recurrent; Doche2013Human).

## Structure
The SH2B1 protein is a multidomain adapter protein involved in various signaling pathways. It contains an SH2 (Src Homology 2) domain, which is crucial for its function in mediating interactions with phosphorylated tyrosine residues on other proteins (McKercher2017Diversity). The SH2 domain exhibits significant structural plasticity, allowing it to recognize a diverse array of peptide ligands. This plasticity is primarily due to the conformational flexibility of several loops, including the EF and BG loops, which can undergo movements up to 10 Å (McKercher2017Diversity). 

The SH2B1 protein also includes a pleckstrin homology (PH) domain, which is involved in membrane association (Aerts2015Genetic). The protein's structure is characterized by a hydrophobic binding groove formed by residues such as V589, L592, I609, and L611, which facilitates the binding of hydrophobic peptide ligands (McKercher2017Diversity). 

SH2B1 is subject to post-translational modifications, including phosphorylation and ubiquitination, and exists in several splice variant isoforms that may differ in their functional roles (Aerts2015Genetic). These structural features and modifications enable SH2B1 to function as a signaling hub, bridging regulatory proteins and forming large signaling complexes (McKercher2017Diversity).

## Function
The SH2B1 gene encodes a multifunctional adaptor protein that plays a crucial role in enhancing insulin sensitivity and signaling in healthy human cells. SH2B1 enhances insulin receptor activity by binding to the receptor's SH2 domain, particularly at phospho-Tyr 1158, which stabilizes the receptor in an active conformation. This interaction promotes the autophosphorylation of the insulin receptor and the tyrosine phosphorylation of insulin receptor substrate proteins (IRS-1 and IRS-2), essential steps in insulin signaling (Morris2009SH2B1). SH2B1 also inhibits the dephosphorylation of IRS proteins, maintaining their phosphorylated state and enhancing their association with the regulatory subunit of phosphatidylinositol 3-kinase (p85), leading to increased Akt phosphorylation and activation (Morris2009SH2B1).

In addition to its role in insulin signaling, SH2B1 is involved in energy balance and body weight regulation by enhancing leptin signaling through the stimulation of JAK2 activity and forming a JAK2/IRS1/2 signaling complex (Rui2014SH2B1). SH2B1 is also implicated in neuronal differentiation and maturation, promoting neurite outgrowth and accelerating the maturation of human induced neurons (Hsu2014Signaling).

## Clinical Significance
Mutations and alterations in the SH2B1 gene are associated with several clinical conditions, primarily obesity and related metabolic disorders. SH2B1 plays a critical role in energy homeostasis and body weight regulation. Loss-of-function mutations in SH2B1 have been linked to severe early-onset obesity, hyperphagia, and insulin resistance in humans. These mutations can also lead to behavioral abnormalities, including social isolation and aggression (Doche2013Human).

Deletions in the 16p11.2 region, which includes SH2B1, are associated with developmental delays and obesity. Patients with these deletions often exhibit high body mass index, speech and motor delays, and intellectual disabilities. Some also present with autism spectrum disorder and seizures (BachmannGagescu2010Recurrent).

Rare variants of SH2B1, such as p.(Val345Met) and p.(Arg630Gln), have been identified in individuals with severe obesity and metabolic syndrome. These variants are considered potentially pathogenic and are linked to conditions like hyperglycemia and hypertension (da2022SH2B1).

Overall, SH2B1 mutations and deletions contribute significantly to obesity and related metabolic and developmental disorders, highlighting its clinical significance in these conditions.

## Interactions
SH2B1 (SH2B adaptor protein 1) is involved in numerous protein-protein interactions, playing a critical role in various signaling pathways. It interacts with the cytokine receptor-associated kinase JAK2, primarily through its SH2 domain, which binds to phosphorylated tyrosine 813 on JAK2. This interaction is essential for JAK2 activation and autophosphorylation, which subsequently phosphorylates SH2B1 on tyrosines, creating binding sites for other signaling proteins (Maures2007SH2B1). SH2B1 also interacts with insulin receptor substrate proteins (IRS1 and IRS2), enhancing insulin sensitivity by inhibiting their dephosphorylation and promoting their association with phosphatidylinositol 3-kinase (Morris2009SH2B1).

SH2B1 forms complexes with JAK2 and IRS proteins, leading to the activation of the PI 3-kinase pathway (Maures2007SH2B1). It also interacts with small GTPase Rac, adaptor proteins Grb2, and ubiquitin ligases like c-Cbl, suggesting roles in cytoskeletal regulation and protein degradation (Maures2007SH2B1). SH2B1 can dimerize, which is crucial for its function in facilitating JAK2 dimerization and activation (Nishi2005Kinase). The protein's ability to shuttle between the nucleus and cytoplasm indicates potential interactions with nuclear proteins, possibly functioning as a transcriptional coactivator (Maures2007SH2B1).


## References


[1. (Nishi2005Kinase) Masahiro Nishi, Eric D. Werner, Byung-Chul Oh, J. Daniel Frantz, Sirano Dhe-Paganon, Lone Hansen, Jongsoon Lee, and Steven E. Shoelson. Kinase activation through dimerization by human sh2-b. Molecular and Cellular Biology, 25(7):2607–2621, April 2005. URL: http://dx.doi.org/10.1128/mcb.25.7.2607-2621.2005, doi:10.1128/mcb.25.7.2607-2621.2005. This article has 45 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/mcb.25.7.2607-2621.2005)

[2. (Maures2007SH2B1) Travis J. Maures, Jason H. Kurzer, and Christin Carter-Su. Sh2b1 (sh2-b) and jak2: a multifunctional adaptor protein and kinase made for each other. Trends in Endocrinology & Metabolism, 18(1):38–45, January 2007. URL: http://dx.doi.org/10.1016/j.tem.2006.11.007, doi:10.1016/j.tem.2006.11.007. This article has 91 citations.](https://doi.org/10.1016/j.tem.2006.11.007)

[3. (da2022SH2B1) Ana Carolina Proença da Fonseca, Izadora Sthephanie Silva Assis, Kaio Cezar Rodrigues Salum, Lohanna Palhinha, Gabriella Medeiros Abreu, Verônica Marques Zembrzuski, Mario Campos Junior, José Firmino Nogueira Neto, Fernanda Cristina C. Mattos, Amanda Cambraia, Eliane Lopes Rosado, Clarissa Menezes Maya-Monteiro, Pedro Hernán Cabello, João Regis Ivar Carneiro, and Patrícia T. Bozza. Sh2b1 variants as potential causes of non-syndromic monogenic obesity in a brazilian cohort. Eating and Weight Disorders - Studies on Anorexia, Bulimia and Obesity, 27(8):3665–3674, November 2022. URL: http://dx.doi.org/10.1007/s40519-022-01506-3, doi:10.1007/s40519-022-01506-3. This article has 1 citations.](https://doi.org/10.1007/s40519-022-01506-3)

[4. (McKercher2017Diversity) Marissa A. McKercher, Xiaoyang Guan, Zhongping Tan, and Deborah S. Wuttke. Diversity in peptide recognition by the sh2 domain of sh2b1. Proteins: Structure, Function, and Bioinformatics, 86(2):164–176, December 2017. URL: http://dx.doi.org/10.1002/prot.25420, doi:10.1002/prot.25420. This article has 3 citations.](https://doi.org/10.1002/prot.25420)

[5. (Rui2014SH2B1) Liangyou Rui. Sh2b1 regulation of energy balance, body weight, and glucose metabolism. World Journal of Diabetes, 5(4):511, 2014. URL: http://dx.doi.org/10.4239/wjd.v5.i4.511, doi:10.4239/wjd.v5.i4.511. This article has 62 citations and is from a peer-reviewed journal.](https://doi.org/10.4239/wjd.v5.i4.511)

[6. (BachmannGagescu2010Recurrent) Ruxandra Bachmann-Gagescu, Heather C. Mefford, Charles Cowan, Gwen M. Glew, Anne V. Hing, Stephanie Wallace, Patricia I. Bader, Aline Hamati, Pamela J. Reitnauer, Rosemarie Smith, David W. Stockton, Hiltrud Muhle, Ingo Helbig, Evan E. Eichler, Blake C. Ballif, Jill Rosenfeld, and Karen D. Tsuchiya. Recurrent 200-kb deletions of 16p11.2 that include the sh2b1 gene are associated with developmental delay and obesity. Genetics in Medicine, 12(10):641–647, October 2010. URL: http://dx.doi.org/10.1097/gim.0b013e3181ef4286, doi:10.1097/gim.0b013e3181ef4286. This article has 157 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1097/gim.0b013e3181ef4286)

[7. (Doche2013Human) Michael E. Doche, Elena G. Bochukova, Hsiao-Wen Su, Laura R. Pearce, Julia M. Keogh, Elana Henning, Joel M. Cline, Sadia Saeed, Anne Dale, Tim Cheetham, Inês Barroso, Lawrence S. Argetsinger, Stephen O’Rahilly, Liangyou Rui, Christin Carter-Su, and I. Sadaf Farooqi. Human sh2b1 mutations are associated with maladaptive behaviors and obesity. Journal of Clinical Investigation, 123(1):526–526, January 2013. URL: http://dx.doi.org/10.1172/jci68022, doi:10.1172/jci68022. This article has 0 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1172/jci68022)

[8. (Morris2009SH2B1) David L. Morris, Kae Won Cho, Yingjiang Zhou, and Liangyou Rui. Sh2b1 enhances insulin sensitivity by both stimulating the insulin receptor and inhibiting tyrosine dephosphorylation of insulin receptor substrate proteins. Diabetes, 58(9):2039–2047, June 2009. URL: http://dx.doi.org/10.2337/db08-1388, doi:10.2337/db08-1388. This article has 72 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.2337/db08-1388)

[9. (Hsu2014Signaling) Yi-Chao Hsu, Su-Liang Chen, Ya-Jean Wang, Yun-Hsiang Chen, Dan-Yen Wang, Linyi Chen, Chia-Hsiang Chen, Hwei-Hsien Chen, and Ing-Ming Chiu. Signaling adaptor protein sh2b1 enhances neurite outgrowth and accelerates the maturation of human induced neurons. Stem Cells Translational Medicine, 3(6):713–722, April 2014. URL: http://dx.doi.org/10.5966/sctm.2013-0111, doi:10.5966/sctm.2013-0111. This article has 11 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.5966/sctm.2013-0111)

[10. (Aerts2015Genetic) Evi Aerts, Sigri Beckers, Doreen Zegers, Jasmijn K. Van Camp, Kim Van Hoorenbeeck, Guy Massa, An Verrijken, Ilse L. Mertens, Stijn L. Verhulst, Raoul R. Rooman, Luc F. Van Gaal, and Wim Van Hul. Genetic and structural variation in the sh2b1 gene in the belgian population. Molecular Genetics and Metabolism, 115(4):193–198, August 2015. URL: http://dx.doi.org/10.1016/j.ymgme.2015.05.010, doi:10.1016/j.ymgme.2015.05.010. This article has 10 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.ymgme.2015.05.010)