Skip to main content

SH2B Adapter Protein 3 (SH2B3)

  • Reference work entry
  • First Online:
Encyclopedia of Signaling Molecules

Synonyms

Lnk; SH2B3

Historical Background

SH2B3 belongs to the Src homology 2B (SH2B) adapter protein family described in the late 1990s. The SH2B family contains three members (SH2B1, SH2B2, and SH2B3) in mammals. SH2B1, SH2B2, and SH2B3 were originally named as SH2-B [also known as SH2 domain-containing signaling mediator (PSM)], adapter protein with PH and SH2 domains (APS) and Lnk, respectively. The SH2B family is evolutionarily conserved from insects through humans. Unlike mammals, insects have only one SH2B gene (also called Lnk or dSH2B). SH2B3 cDNA was initially cloned and characterized in rat and then in mice in 1997 by Takaki and colleagues who described the first transgenic mice for Lnk/SH2B3 and established SH2B3 as a regulator of signaling in T and B cells (Takaki et al. 1997). Subsequent studies revealed a more widespread role for SH2B3 in myeloid development and hematopoiesis. The deduced amino acid sequences of mouse and rat SH2B3 share 96% identity and 98% similarity...

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 4,499.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 4,499.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Almudi I, Poernbacher I, Hafen E, Stocker H. The Lnk/SH2B adaptor provides a fail-safe mechanism to establish the Insulin receptor-Chico interaction. Cell Commun Signal. 2013;11:26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bersenev A, Wu C, Balcerek J, Tong W. Lnk controls mouse hematopoietic stem cell self-renewal and quiescence through direct interactions with JAK2. J Clin Invest. 2008;118:2832–44.

    PubMed  PubMed Central  CAS  Google Scholar 

  • Boulday G, Coulon F, Fraser CC, Soulillou JP, Charreau B. Transcriptional up-regulation of the signaling regulatory protein LNK in activated endothelial cells. Transplantation. 2002;74:1352–4.

    Article  PubMed  CAS  Google Scholar 

  • Cheng Y, Chikwava K, Wu C, Zhang H, Bhagat A, Pei D, Choi JK, Tong W. LNK/SH2B3 regulates IL-7 receptor signaling in normal and malignant B-progenitors. J Clin Invest. 2016;126:1267–81.

    Article  PubMed  PubMed Central  Google Scholar 

  • Dale BL, Madhur MS. Linking inflammation and hypertension via LNK/SH2B3. Curr Opin Nephrol Hypertens. 2016;25:87–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Devalliere J, Chatelais M, Fitau J, Gerard N, Hulin P, Velazquez L, Turner CE, Charreau B. LNK (SH2B3) is a key regulator of integrin signaling in endothelial cells and targets alpha-parvin to control cell adhesion and migration. FASEB J. 2012;26:2592–606.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ding LW, Sun QY, Lin DC, Chien W, Hattori N, Dong XM, Gery S, Garg M, Doan NB, Said JW, Xiao JF, Yang H, Liu LZ, Meng X, Huang RY, Tang K, Koeffler HP. LNK (SH2B3): paradoxical effects in ovarian cancer. Oncogene. 2015;34:1463–74.

    Article  PubMed  CAS  Google Scholar 

  • Fitau J, Boulday G, Coulon F, Quillard T, Charreau B. The adaptor molecule Lnk negatively regulates tumor necrosis factor-alpha-dependent VCAM-1 expression in endothelial cells through inhibition of the ERK1 and −2 pathways. J Biol Chem. 2006;281:20148–59.

    Article  PubMed  CAS  Google Scholar 

  • Fortney K, Dobriban E, Garagnani P, Pirazzini C, Monti D, Mari D, Atzmon G, Barzilai N, Franceschi C, Owen AB, Kim SK. Genome-wide scan informed by age-related disease identifies loci for exceptional human longevity. PLoS Genet. 2015;11:e1005728.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gery S, Gueller S, Chumakova K, Kawamata N, Liu L, Koeffler HP. Adaptor protein Lnk negatively regulates the mutant MPL, MPLW515L associated with myeloproliferative disorders. Blood. 2007;110:3360–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gery S, Gueller S, Nowak V, Sohn J, Hofmann WK, Koeffler HP. Expression of the adaptor protein Lnk in leukemia cells. Exp Hematol. 2009;37:585–592e582.

    Article  PubMed  CAS  Google Scholar 

  • Hunt KA, Zhernakova A, Turner G, Heap GA, Franke L, Bruinenberg M, Romanos J, Dinesen LC, Ryan AW, Panesar D, Gwilliam R, Takeuchi F, McLaren WM, Holmes GK, Howdle PD, Walters JR, Sanders DS, Playford RJ, Trynka G, Mulder CJ, Mearin ML, Verbeek WH, Trimble V, Stevens FM, O’Morain C, Kennedy NP, Kelleher D, Pennington DJ, Strachan DP, McArdle WL, Mein CA, Wapenaar MC, Deloukas P, McGinnis R, McManus R, Wijmenga C, van Heel DA. Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet. 2008;40:395–402.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kubo-Akashi C, Iseki M, Kwon SM, Takizawa H, Takatsu K, Takaki S. Roles of a conserved family of adaptor proteins, Lnk, SH2-B, and APS, for mast cell development, growth, and functions: APS-deficiency causes augmented degranulation and reduced actin assembly. Biochem Biophys Res Commun. 2004;315:356–62.

    Article  PubMed  CAS  Google Scholar 

  • Kwon SM, Suzuki T, Kawamoto A, Ii M, Eguchi M, Akimaru H, Wada M, Matsumoto T, Masuda H, Nakagawa Y, Nishimura H, Kawai K, Takaki S, Asahara T. Pivotal role of lnk adaptor protein in endothelial progenitor cell biology for vascular regeneration. Circ Res. 2009;104:969–77.

    Article  PubMed  CAS  Google Scholar 

  • Levy D, Ehret GB, Rice K, Verwoert GC, Launer LJ, Dehghan A, Glazer NL, Morrison AC, Johnson AD, Aspelund T, Aulchenko Y, Lumley T, Kottgen A, Vasan RS, Rivadeneira F, Eiriksdottir G, Guo X, Arking DE, Mitchell GF, Mattace-Raso FU, Smith AV, Taylor K, Scharpf RB, Hwang SJ, Sijbrands EJ, Bis J, Harris TB, Ganesh SK, O’Donnell CJ, Hofman A, Rotter JI, Coresh J, Benjamin EJ, Uitterlinden AG, Heiss G, Fox CS, Witteman JC, Boerwinkle E, Wang TJ, Gudnason V, Larson MG, Chakravarti A, Psaty BM, van Duijn CM. Genome-wide association study of blood pressure and hypertension. Nat Genet. 2009;41:677–87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Louria-Hayon I, Frelin C, Ruston J, Gish G, Jin J, Kofler MM, Lambert JP, Adissu HA, Milyavsky M, Herrington R, Minden MD, Dick JE, Gingras AC, Iscove NN, Pawson T. Lnk adaptor suppresses radiation resistance and radiation-induced B-cell malignancies by inhibiting IL-11 signaling. Proc Natl Acad Sci USA. 2013;110:20599–604.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • McMullin MF, Cario H. LNK mutations and myeloproliferative disorders. Am J Hematol. 2016;91:248–51.

    Article  PubMed  CAS  Google Scholar 

  • Nobuhisa I, Takizawa M, Takaki S, Inoue H, Okita K, Ueno M, Takatsu K, Taga T. Regulation of hematopoietic development in the aorta-gonad-mesonephros region mediated by Lnk adaptor protein. Mol Cell Biol. 2003;23:8486–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Oh ST. When the Brakes are Lost: LNK Dysfunction in Mice, Men, and Myeloproliferative Neoplasms. Therap Adv Hematol. 2011;2:11–9.

    Article  CAS  Google Scholar 

  • Oh ST, Simonds EF, Jones C, Hale MB, Goltsev Y, Gibbs Jr KD, Merker JD, Zehnder JL, Nolan GP, Gotlib J. Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms. Blood. 2010;116:988–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pardanani A, Lasho T, Finke C, Oh ST, Gotlib J, Tefferi A. LNK mutation studies in blast-phase myeloproliferative neoplasms, and in chronic-phase disease with TET2, IDH, JAK2 or MPL mutations. Leukemia. 2010;24:1713–8.

    Article  PubMed  CAS  Google Scholar 

  • Roberts KG, Li Y, Payne-Turner D, Harvey RC, Yang YL, Pei D, McCastlain K, Ding L, Lu C, Song G, Ma J, Becksfort J, Rusch M, Chen SC, Easton J, Cheng J, Boggs K, Santiago-Morales N, Iacobucci I, Fulton RS, Wen J, Valentine M, Cheng C, Paugh SW, Devidas M, Chen IM, Reshmi S, Smith A, Hedlund E, Gupta P, Nagahawatte P, Wu G, Chen X, Yergeau D, Vadodaria B, Mulder H, Winick NJ, Larsen EC, Carroll WL, Heerema NA, Carroll AJ, Grayson G, Tasian SK, Moore AS, Keller F, Frei-Jones M, Whitlock JA, Raetz EA, White DL, Hughes TP, Guidry Auvil JM, Smith MA, Marcucci G, Bloomfield CD, Mrozek K, Kohlschmidt J, Stock W, Kornblau SM, Konopleva M, Paietta E, Pui CH, Jeha S, Relling MV, Evans WE, Gerhard DS, Gastier-Foster JM, Mardis E, Wilson RK, Loh ML, Downing JR, Hunger SP, Willman CL, Zhang J, Mullighan CG. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med. 2014;371:1005–15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Saleh MA, McMaster WG, Wu J, Norlander AE, Funt SA, Thabet SR, Kirabo A, Xiao L, Chen W, Itani HA, Michell D, Huan T, Zhang Y, Takaki S, Titze J, Levy D, Harrison DG, Madhur MS. Lymphocyte adaptor protein LNK deficiency exacerbates hypertension and end-organ inflammation. J Clin Invest. 2015;125:1189–202.

    Article  PubMed  PubMed Central  Google Scholar 

  • Slack C, Werz C, Wieser D, Alic N, Foley A, Stocker H, Withers DJ, Thornton JM, Hafen E, Partridge L. Regulation of lifespan, metabolism, and stress responses by the Drosophila SH2B protein, Lnk. PLoS Genet. 2010;6:e1000881.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Takaki S, Watts JD, Forbush KA, Nguyen NT, Hayashi J, Alberola-Ila J, Aebersold R, Perlmutter RM. Characterization of Lnk. An adaptor protein expressed in lymphocytes. J Biol Chem. 1997;272:14562–70.

    Article  PubMed  CAS  Google Scholar 

  • Takaki S, Morita H, Tezuka Y, Takatsu K. Enhanced hematopoiesis by hematopoietic progenitor cells lacking intracellular adaptor protein, Lnk. J Exp Med. 2002;195:151–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Takaki S, Tezuka Y, Sauer K, Kubo C, Kwon SM, Armstead E, Nakao K, Katsuki M, Perlmutter RM, Takatsu K. Impaired lymphopoiesis and altered B cell subpopulations in mice overexpressing Lnk adaptor protein. J Immunol. 2003;170:703–10.

    Article  PubMed  CAS  Google Scholar 

  • Takizawa H, Kubo-Akashi C, Nobuhisa I, Kwon SM, Iseki M, Taga T, Takatsu K, Takaki S. Enhanced engraftment of hematopoietic stem/progenitor cells by the transient inhibition of an adaptor protein, Lnk. Blood. 2006;107:2968–75.

    Article  PubMed  CAS  Google Scholar 

  • Takizawa H, Nishimura S, Takayama N, Oda A, Nishikii H, Morita Y, Kakinuma S, Yamazaki S, Okamura S, Tamura N, Goto S, Sawaguchi A, Manabe I, Takatsu K, Nakauchi H, Takaki S, Eto K. Lnk regulates integrin alphaIIbbeta3 outside-in signaling in mouse platelets, leading to stabilization of thrombus development in vivo. J Clin Invest. 2010;120:179–90.

    Article  PubMed  CAS  Google Scholar 

  • Velazquez L, Cheng AM, Fleming HE, Furlonger C, Vesely S, Bernstein A, Paige CJ, Pawson T. Cytokine signaling and hematopoietic homeostasis are disrupted in Lnk-deficient mice. J Exp Med. 2002;195:1599–611.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wang W, Tang Y, Wang Y, Tascau L, Balcerek J, Tong W, Levine RL, Welch C, Tall AR, Wang N. LNK/SH2B3 loss of function promotes atherosclerosis and thrombosis. Circ Res. 2016;119:e91–e103.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Westra HJ, Peters MJ, Esko T, Yaghootkar H, Schurmann C, Kettunen J, Christiansen MW, Fairfax BP, Schramm K, Powell JE, Zhernakova A, Zhernakova DV, Veldink JH, Van den Berg LH, Karjalainen J, Withoff S, Uitterlinden AG, Hofman A, Rivadeneira F, Hoen PA’t, Reinmaa E, Fischer K, Nelis M, Milani L, Melzer D, Ferrucci L, Singleton AB, Hernandez DG, Nalls MA, Homuth G, Nauck M, Radke D, Volker U, Perola M, Salomaa V, Brody J, Suchy-Dicey A, Gharib SA, Enquobahrie DA, Lumley T, Montgomery GW, Makino S, Prokisch H, Herder C, Roden M, Grallert H, Meitinger T, Strauch K, Li Y, Jansen RC, Visscher PM, Knight JC, Psaty BM, Ripatti S, Teumer A, Frayling TM, Metspalu A, van Meurs JB, Franke L. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet. 2013;45:1238–43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhernakova A, Elbers CC, Ferwerda B, Romanos J, Trynka G, Dubois PC, de Kovel CG, Franke L, Oosting M, Barisani D, Bardella MT, Joosten LA, Saavalainen P, van Heel DA, Catassi C, Netea MG, Wijmenga C. Evolutionary and functional analysis of celiac risk loci reveals SH2B3 as a protective factor against bacterial infection. Am J Hum Genet. 2010;86:970–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgments

This work was realized in the context of the IHU-Cesti, LabEx IGO, and LabEx Transplantex projects which received French government financial support managed by the National Research Agency (ANR) via the “Investment Into The Future” programs ANR-10-IBHU-005, ANR-11-LABX-0016-01, and ANR-11-LABX-0070. The IHU-Cesti project is also supported by Nantes Metropole and the Pays de la Loire Region. This study is also supported by the Region Pays de la Loire, the “Fondation Centaure” (RTRS) which supports a French transplantation research network and by The Agence de la Biomédecine. I apologize that all references could not be cited due to space restrictions.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Béatrice L. Charreau .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Charreau, B.L. (2018). SH2B Adapter Protein 3 (SH2B3). In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, Cham. https://doi.org/10.1007/978-3-319-67199-4_101847

Download citation

Publish with us

Policies and ethics