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SH2B3

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SH2B3
Identifiers
AliasesSH2B3, IDDM20, LNK, SH2B adaptor protein 3
External IDsOMIM: 605093; MGI: 893598; HomoloGene: 36179; GeneCards: SH2B3; OMA:SH2B3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

10019

16923

Ensembl

ENSG00000111252

ENSMUSG00000042594

UniProt

Q9UQQ2

O09039

RefSeq (mRNA)

NM_001291424
NM_005475

NM_008507
NM_001306126
NM_001306127
NM_001306128

RefSeq (protein)

NP_001278353
NP_005466

NP_001293055
NP_001293056
NP_001293057
NP_032533

Location (UCSC)Chr 12: 111.41 – 111.45 MbChr 5: 121.95 – 121.98 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

SH2B adapter protein 3 (SH2B3), also known as lymphocyte adapter protein (LNK), is a protein that in humans is encoded by the SH2B3 gene on chromosome 12.[5][6] SH2B3 is ubiquitously expressed in many tissues and cell types.[7] LNK functions as a regulator in signaling pathways relating to hematopoiesis, inflammation, and cell migration.[8] As a result, it is involved in blood diseases, autoimmune disorders, and vascular disease.[9] The SH2B3 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.[10]

Structure

Gene

The SH2B3 gene resides on chromosome 12 at the band 12q24 and contains 12 exons.[6]

Protein

This protein belongs to the Src homology 2-B (SH2B) adapter family.[8][11] LNK contains 3 functional domains: a C-terminal Src homology 2 (SH2) domain,[12] a pleckstrin homology (PH) domain, and a dimerization domain. The SH2 domain spans approximately 100 amino acid residues and binds phosphotyrosine-containing proteins such as kinases. The PH domain spans approximately 120 amino acid residues and binds the phosphatidylinositol lipids found in the cell membrane. Thus, it is proposed to target the protein to the cell membrane, where LNK performs its regulatory function. The dimerization domain spans approximately 70 amino acid residues and contains a central phenylalanine zipper motif, which is formed by stacking of the aromatic side chains from 10 phenylalanine residues. This motif is responsible for facilitating the homo- or heterodimerization of SH2-B family proteins as a mechanism for regulating signal transduction. In addition to these domains, LNK possesses a proline-rich region that contains a minimal consensus sequence of Pro-X-X-Pro, which is recognized by the SH3 domain of another protein, as well as putative tyrosine phosphorylation motifs.[8]

Function

LNK is widely expressed in human tissues, with the highest expression in hematopoietic cells. LNK negatively controls the activation of several receptors, including stem cell factor receptor (c-kit),[13] thrombopoietin receptor (MPL),[14] erythropoietin receptor (EPOR),[15] platelet-derived growth factor receptor (PDGFR),[16] macrophage colony-stimulating factor receptor (c-Fms),[17] and their related pathways. LNK is a negative regulator of signaling in endothelial cells, such as the TNF signaling pathway, especially in inflammation. LNK has been found to function as a negative regulator in lymphopoiesis, megakaryopoiesis, erythropoiesis as well as HSC expansion by moderating growth factor and cytokine receptor-mediated signaling.[8] The overexpression of LNK led to the inhibition of anti-CD3 mediated NF-AT-Luc activation, indicating that LNK is involved in the mechanism of T cell-negative regulation.[18] In addition to its role in progenitor cell growth and commitment, LNK appears to be involved in cell motility and cellular interactions. LNK modulates crosstalk between integrin- and cytokine-mediated signals, thus controlling thrombopoiesis.[19] LNK facilitates integrin aIIbb3 phosphorylation and signaling in order to promote platelet cytoskeleton rearrangement and spreading, and thus stabilizes thrombosis formation.[20]

Interactions

SH2B3 has been shown to interact with Filamin.[21]

Clinical significance

In humans, genetic linkage analyses, genome-wide association studies of single nucleotide polymorphisms, copy number variation surveys, and mutation screenings found the human chromosomal 12q24 locus, with the SH2B3 gene at its core, to be associated with an exceptionally wide spectrum of disease susceptibilities. For example, hematopoietic traits of red and white blood cells (like erythrocytosis and myeloproliferative disease), autoimmune disorders, and vascular pathology have been reported.[9] Moreover, co-expression of the interleukin-7 receptor together with LNK was carefully studied, and it was concluded that interleukin-7 receptor expression was significantly more highly expressed than LNK in B-cell acute leukemic lymphoma. This observation distinguished a novel subset of high-risk B-cell acute lymphoblastic lymphoma[22] with a potential therapy targeting the interleukin-7 signaling pathway. Another study indicated that LNK can suppress the interleukin-7/JAK/STAT signaling pathway to restrict pre B-cell progenitor expansion and leukemia development, which provided a pathogenic mechanism and a potential therapeutic approach for B-cell acute lymphoblastic leukemia with SH2B3 gene mutations.[23]

Clinical marker

A multi-locus genetic risk score study based on a combination of 27 loci, including the SH2B3 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).[10]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000111252 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000042594 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Li Y, He X, Schembri-King J, Jakes S, Hayashi J (May 2000). "Cloning and characterization of human Lnk, an adaptor protein with pleckstrin homology and Src homology 2 domains that can inhibit T cell activation". Journal of Immunology. 164 (10): 5199–206. doi:10.4049/jimmunol.164.10.5199. PMID 10799879.
  6. ^ a b "Entrez Gene: SH2B3 SH2B adaptor protein 3".
  7. ^ "BioGPS - your Gene Portal System". biogps.org. Retrieved 2016-10-11.
  8. ^ a b c d Devallière J, Charreau B (November 2011). "The adaptor Lnk (SH2B3): an emerging regulator in vascular cells and a link between immune and inflammatory signaling". Biochemical Pharmacology. 82 (10): 1391–402. doi:10.1016/j.bcp.2011.06.023. PMID 21723852.
  9. ^ a b Auburger G, Gispert S, Lahut S, Omür O, Damrath E, Heck M, Başak N (June 2014). "12q24 locus association with type 1 diabetes: SH2B3 or ATXN2?". World Journal of Diabetes. 5 (3): 316–27. doi:10.4239/wjd.v5.i3.316. PMC 4058736. PMID 24936253.
  10. ^ a b Mega JL, Stitziel NO, Smith JG, Chasman DI, Caulfield MJ, Devlin JJ, Nordio F, Hyde CL, Cannon CP, Sacks FM, Poulter NR, Sever PS, Ridker PM, Braunwald E, Melander O, Kathiresan S, Sabatine MS (June 2015). "Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials". Lancet. 385 (9984): 2264–71. doi:10.1016/S0140-6736(14)61730-X. PMC 4608367. PMID 25748612.
  11. ^ "SH2B3 - SH2B adapter protein 3 - Homo sapiens (Human) - SH2B3 gene & protein". www.uniprot.org. Retrieved 2016-10-11.
  12. ^ Morris R, Zhang Y, Ellyard JI, Vinuesa CG, Murphy JM, Laktyushin A, et al. (October 2021). "Structural and functional analysis of target recognition by the lymphocyte adaptor protein LNK". Nature Communications. 12 (1): 6110. Bibcode:2021NatCo..12.6110M. doi:10.1038/s41467-021-26394-6. PMC 8528861. PMID 34671038.
  13. ^ Takaki S, Morita H, Tezuka Y, Takatsu K (January 2002). "Enhanced hematopoiesis by hematopoietic progenitor cells lacking intracellular adaptor protein, Lnk". The Journal of Experimental Medicine. 195 (2): 151–60. doi:10.1084/jem.20011170. PMC 2193601. PMID 11805142.
  14. ^ Seita J, Ema H, Ooehara J, Yamazaki S, Tadokoro Y, Yamasaki A, Eto K, Takaki S, Takatsu K, Nakauchi H (February 2007). "Lnk negatively regulates self-renewal of hematopoietic stem cells by modifying thrombopoietin-mediated signal transduction". Proceedings of the National Academy of Sciences of the United States of America. 104 (7): 2349–54. Bibcode:2007PNAS..104.2349S. doi:10.1073/pnas.0606238104. PMC 1892983. PMID 17284614.
  15. ^ Tong W, Zhang J, Lodish HF (June 2005). "Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways". Blood. 105 (12): 4604–12. doi:10.1182/blood-2004-10-4093. PMC 1894992. PMID 15705783.
  16. ^ Gueller S, Hehn S, Nowak V, Gery S, Serve H, Brandts CH, Koeffler HP (May 2011). "Adaptor protein Lnk binds to PDGF receptor and inhibits PDGF-dependent signaling". Experimental Hematology. 39 (5): 591–600. doi:10.1016/j.exphem.2011.02.001. PMID 21310211.
  17. ^ Gueller S, Goodridge HS, Niebuhr B, Xing H, Koren-Michowitz M, Serve H, Underhill DM, Brandts CH, Koeffler HP (October 2010). "Adaptor protein Lnk inhibits c-Fms-mediated macrophage function". Journal of Leukocyte Biology. 88 (4): 699–706. doi:10.1189/jlb.0309185. PMC 3218676. PMID 20571037.
  18. ^ Li Y, He X, Schembri-King J, Jakes S, Hayashi J (May 2000). "Cloning and characterization of human Lnk, an adaptor protein with pleckstrin homology and Src homology 2 domains that can inhibit T cell activation" (PDF). Journal of Immunology. 164 (10): 5199–206. doi:10.4049/jimmunol.164.10.5199. PMID 10799879. S2CID 24880870.
  19. ^ Takizawa H, Eto K, Yoshikawa A, Nakauchi H, Takatsu K, Takaki S (July 2008). "Growth and maturation of megakaryocytes is regulated by Lnk/Sh2b3 adaptor protein through crosstalk between cytokine- and integrin-mediated signals". Experimental Hematology. 36 (7): 897–906. doi:10.1016/j.exphem.2008.02.004. PMID 18456388.
  20. ^ Shattil SJ, Newman PJ (September 2004). "Integrins: dynamic scaffolds for adhesion and signaling in platelets". Blood. 104 (6): 1606–15. doi:10.1182/blood-2004-04-1257. PMID 15205259.
  21. ^ He X, Li Y, Schembri-King J, Jakes S, Hayashi J (August 2000). "Identification of actin binding protein, ABP-280, as a binding partner of human Lnk adaptor protein". Molecular Immunology. 37 (10): 603–12. doi:10.1016/S0161-5890(00)00070-5. PMID 11163396.
  22. ^ Ge Z, Gu Y, Xiao L, Han Q, Li J, Chen B, Yu J, Kawasawa YI, Payne KJ, Dovat S, Song C (June 2016). "Co-existence of IL7R high and SH2B3 low expression distinguishes a novel high-risk acute lymphoblastic leukemia with Ikaros dysfunction". Oncotarget. 7 (29): 46014–46027. doi:10.18632/oncotarget.10014. PMC 5216778. PMID 27322554.
  23. ^ Cheng Y, Chikwava K, Wu C, Zhang H, Bhagat A, Pei D, Choi JK, Tong W (April 2016). "LNK/SH2B3 regulates IL-7 receptor signaling in normal and malignant B-progenitors". The Journal of Clinical Investigation. 126 (4): 1267–81. doi:10.1172/JCI81468. PMC 4811117. PMID 26974155.

Further reading

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