SH2B adapter protein 3 (SH2B3), also known as lymphocyte adapter protein (LNK), is a protein that in humans is encoded by the SH2B3gene on chromosome 12.[1][2]
The SH2B3 gene resides on chromosome 12 at the band 12q24 and contains 12 exons.[2]
Protein
This protein belongs to the Src homology 2-B (SH2B) adapter family.[4][7] LNK contains 3 functional domains: a C-terminal Src homology 2 (SH2) domain, 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.[4]
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.[5] 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[17] 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.[18]
Clinical marker
A multi-locus genetic risk score study based on a combination of 27 loci, including the SBH2B3 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).[6]
References
↑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. PMID10799879.
↑ 4.04.14.24.3Devallière 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. PMID21723852.
↑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. PMID18456388.
↑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. PMID15205259.
↑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. PMID11163396.
Hendricks-Taylor LR, Motto DG, Zhang J, Siraganian RP, Koretzky GA (January 1997). "SLP-76 is a substrate of the high affinity IgE receptor-stimulated protein tyrosine kinases in rat basophilic leukemia cells". The Journal of Biological Chemistry. 272 (2): 1363–7. doi:10.1074/jbc.272.2.1363. PMID8995445.
Takaki S, Watts JD, Forbush KA, Nguyen NT, Hayashi J, Alberola-Ila J, Aebersold R, Perlmutter RM (June 1997). "Characterization of Lnk. An adaptor protein expressed in lymphocytes". The Journal of Biological Chemistry. 272 (23): 14562–70. doi:10.1074/jbc.272.23.14562. PMID9169414.
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. PMID11163396.
Fitau J, Boulday G, Coulon F, Quillard T, Charreau B (July 2006). "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". The Journal of Biological Chemistry. 281 (29): 20148–59. doi:10.1074/jbc.M510997200. PMID16644735.
Wan M, Li Y, Xue H, Li Q, Li J (November 2006). "TNF-alpha induces Lnk expression through PI3K-dependent signaling pathway in human umbilical vein endothelial cells". The Journal of Surgical Research. 136 (1): 53–7. doi:10.1016/j.jss.2006.07.004. PMID17007883.