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Gene Review

SH2B2  -  SH2B adaptor protein 2

Homo sapiens

Synonyms: APS, Adapter protein with pleckstrin homology and Src homology 2 domains, SH2 and PH domain-containing adapter protein APS, SH2B adapter protein 2
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Disease relevance of SH2B2

  • APS expressed only in human Burkitt's lymphoma cells among cell lines we examined and tyrosine phosphorylated in response to BCR stimulation [1].
  • Here we report that APS was expressed in some human osteosarcoma cell lines, markedly so in SaOS-2 cells, and was tyrosine-phosphorylated in response to several growth factors, including platelet derived growth factor (PDGF), insulin-like growth factor (IGF), and granulocyte-macrophage colony stimulating factor (GM-CSF) [2].
  • Patients with thrombocytopenia from various causes (n = 50), systemic lupus erythematosus (SLE; n = 40), and the antiphospholipid antibody syndrome (APS; n = 55) had prevalences of IgG antibodies of 8%, 13%, and 5% respectively, only slightly higher than the prevalence in 111 healthy donors (4%) [3].
  • The APS supplies nerves IX, X, XI and XII; XI has a dual vascularization which explains why it can either be spared (as was the case in an angiographic accident) or involved (as in a case of herpes zoster) [4].
  • This may have important implications in treatment of thrombosis in APS patients [5].

Psychiatry related information on SH2B2

  • Factor analysis yielded a 2-factor solution for the AAS (Acknowledgement of Alcohol/Drug Problems; Positive Alcohol Expectancies) and a 4-factor solution for the APS (Satisfaction with Self; Cynicism/Pessimism; Impulsivity; Risk-Taking) [6].

High impact information on SH2B2

  • ATP sulfurylase/APS kinase catalyses the metabolic activation of inorganic sulfate to PAPS, the universal donor for post-translational protein sulfation in all cell types [7].
  • We identified two orthologous genes, ATPSK2 and Atpsk2, encoding novel ATP sulfurylase/APS kinase orthologues in the respective regions of the human and mouse genomes [7].
  • An essential step in this pathway is the activation of sulfate through adenylation by the enzyme ATP sulfurylase (ATPS), forming adenosine 5'-phosphosulfate (APS) [8].
  • Proteobacterial ATPS overcomes this energetically unfavorable reaction by associating with a regulatory G protein, coupling the energy of GTP hydrolysis to APS formation [8].
  • Here, we present the crystal structure of the APS SH2 domain in complex with the phosphorylated tyrosine kinase domain of the insulin receptor [9].

Chemical compound and disease context of SH2B2


Biological context of SH2B2

  • APS, an adaptor protein containing Pleckstrin homology (PH) and Src homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration with c-Cbl [14].
  • This required the C-terminal phosphorylation site, as well as PH and SH2 domains of APS [14].
  • APS is phosphorylated by the insulin receptor on a C-terminal tyrosine residue, which then serves as a binding site for the Cbl TKB domain [15].
  • We found that the adaptor molecule APS could bind the CH domain of Vav3, a member of the vav proto-oncogene family [16].
  • Mouse APS gene consists of 8 coding exons and is deduced to map to chromosome 5 [17].

Anatomical context of SH2B2

  • We cloned a novel adaptor protein, APS (adaptor molecule containing Pleckstrin homology (PH) and Src Homology-2 (SH2) domains), which was tyrosine phosphorylated in response to c-kit or B cell receptor stimulation [14].
  • APS mRNA and protein are expressed primarily in skeletal muscle, heart, and adipose tissue, and in differentiated 3T3-L1 adipocytes [18].
  • Here we demonstrate, by use of immobilized synthetic phosphopeptides corresponding to various autophosphorylated tyrosine residues in the receptor for stem-cell factor (c-Kit), that APS preferentially associates with phosphorylated Tyr-568 and Tyr-936 [19].
  • APS transcripts are expressed in various tissues including brain, kidney, and muscle, as well as in splenic B cells but not in T cells [20].
  • Finally, recombinant enzyme expressed in COS-1 cells exhibited both ATP sulfurylase and APS kinase activity [21].

Associations of SH2B2 with chemical compounds

  • APS bound to the phosphorylated tyrosine residue, Y343 of the erythropoietin receptor cytoplasmic domain [14].
  • Structural characterization of a novel Cbl phosphotyrosine recognition motif in the APS family of adapter proteins [15].
  • Adaptor protein APS binds the NH2-terminal autoinhibitory domain of guanine nucleotide exchange factor Vav3 and augments its activity [16].
  • The adaptor protein APS is a substrate of the insulin receptor and couples receptor activation with phosphorylation of Cbl to facilitate glucose uptake [9].
  • This structure documents how adjacent negative charges are stabilized by the protein matrix which is crucial for forming APS from AMP and sulfite in the reverse reaction [22].

Physical interactions of SH2B2


Regulatory relationships of SH2B2


Other interactions of SH2B2

  • Based on the G, C profile an isochore switch can be defined between the CUTL1 gene and the APS and PMSL12 genes [23].
  • Focus formation assays demonstrated that APS could increase the transforming activity of proto-Vav3 [16].
  • Indeed, tyrosine phosphorylation of PLC-gamma, which has been demonstrated to bind to pY1021, but not that of PI3 kinase and associated proteins, was reduced in APS transformants [2].
  • Phosphotyrosine 936, also in the distal kinase domain, binds the adaptor proteins APS, Grb2, and Grb7 [24].
  • Using x-ray crystallography, site-directed mutagenesis, and calorimetric studies, we have characterized the interaction between the Cbl TKB domain and the Cbl recruitment site in APS, which contains a sequence motif, RA(V/I)XNQpY(S/T), that is conserved in the related adapter proteins SH2-B and Lnk [15].

Analytical, diagnostic and therapeutic context of SH2B2

  • Molecular cloning of the mouse APS as a member of the Lnk family adaptor proteins [17].
  • BACKGROUND: Radiofrequency catheter ablation of concealed posteroseptal accessory pathways (APS) has been a relatively difficult task for electrophysiologists [25].
  • DQB1*0303-DRB1*0701 haplotype was associated with TNFA-238*A in the control group (OR 96.0 [95% CI 9.6-959], p <0.0001) as well as in APS patient's group (OR 54.2 [95% CI 9.6-306.5], p <0.0001) [26].
  • Sera from 39 patients with APS I, diluted 1:150, were used in indirect immunofluorescence staining of cryo-sections from normal human scalp [27].
  • A newly developed PCR assay was used to amplify and sequence a fragment ( approximately 900 bp) of the APS reductase gene, apsA, from a taxonomically wide range of sulfate-reducing prokaryotes (n = 60) [28].


  1. Cloning and characterization of APS, an adaptor molecule containing PH and SH2 domains that is tyrosine phosphorylated upon B-cell receptor stimulation. Yokouchi, M., Suzuki, R., Masuhara, M., Komiya, S., Inoue, A., Yoshimura, A. Oncogene (1997) [Pubmed]
  2. APS, an adaptor protein containing PH and SH2 domains, is associated with the PDGF receptor and c-Cbl and inhibits PDGF-induced mitogenesis. Yokouchi, M., Wakioka, T., Sakamoto, H., Yasukawa, H., Ohtsuka, S., Sasaki, A., Ohtsubo, M., Valius, M., Inoue, A., Komiya, S., Yoshimura, A. Oncogene (1999) [Pubmed]
  3. ADAMTS13 autoantibodies in patients with thrombotic microangiopathies and other immunomediated diseases. Rieger, M., Mannucci, P.M., Kremer Hovinga, J.A., Herzog, A., Gerstenbauer, G., Konetschny, C., Zimmermann, K., Scharrer, I., Peyvandi, F., Galbusera, M., Remuzzi, G., Böhm, M., Plaimauer, B., Lämmle, B., Scheiflinger, F. Blood (2005) [Pubmed]
  4. Cranial nerve ischaemic arterial syndromes. A review. Lapresle, J., Lasjaunias, P. Brain (1986) [Pubmed]
  5. Hydroxychloroquine reverses platelet activation induced by human IgG antiphospholipid antibodies. Espinola, R.G., Pierangeli, S.S., Gharavi, A.E., Harris, E.N., Ghara, A.E. Thromb. Haemost. (2002) [Pubmed]
  6. Diagnostic accuracy and factor structure of the AAS and APS scales of the MMPI-2. Clements, R., Heintz, J.M. Journal of personality assessment. (2002) [Pubmed]
  7. Mutations in orthologous genes in human spondyloepimetaphyseal dysplasia and the brachymorphic mouse. ul Haque, M.F., King, L.M., Krakow, D., Cantor, R.M., Rusiniak, M.E., Swank, R.T., Superti-Furga, A., Haque, S., Abbas, H., Ahmad, W., Ahmad, M., Cohn, D.H. Nat. Genet. (1998) [Pubmed]
  8. Molecular basis for G protein control of the prokaryotic ATP sulfurylase. Mougous, J.D., Lee, D.H., Hubbard, S.C., Schelle, M.W., Vocadlo, D.J., Berger, J.M., Bertozzi, C.R. Mol. Cell (2006) [Pubmed]
  9. Structural basis for recruitment of the adaptor protein APS to the activated insulin receptor. Hu, J., Liu, J., Ghirlando, R., Saltiel, A.R., Hubbard, S.R. Mol. Cell (2003) [Pubmed]
  10. Differential role of SH2-B and APS in regulating energy and glucose homeostasis. Li, M., Ren, D., Iseki, M., Takaki, S., Rui, L. Endocrinology (2006) [Pubmed]
  11. Enzymes of dimethylsulfone metabolism and the phylogenetic characterization of the facultative methylotrophs Arthrobacter sulfonivorans sp. nov., Arthrobacter methylotrophus sp. nov., and Hyphomicrobium sulfonivorans sp. nov. Borodina, E., Kelly, D.P., Schumann, P., Rainey, F.A., Ward-Rainey, N.L., Wood, A.P. Arch. Microbiol. (2002) [Pubmed]
  12. Antiphosphatidylserine antibodies are elevated in normal tension glaucoma. Kremmer, S., Kreuzfelder, E., Klein, R., Bontke, N., Henneberg-Quester, K.B., Steuhl, K.P., Grosse-Wilde, H. Clin. Exp. Immunol. (2001) [Pubmed]
  13. A study on the reaction mechanism of adenosine 5'-phosphosulfate reductase from Thiobacillus thioparus, an iron-sulfur flavoprotein. Adachi, K., Suzuki, I. Can. J. Biochem. (1977) [Pubmed]
  14. APS, an adaptor protein containing Pleckstrin homology (PH) and Src homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration with c-Cbl. Wakioka, T., Sasaki, A., Mitsui, K., Yokouchi, M., Inoue, A., Komiya, S., Yoshimura, A. Leukemia (1999) [Pubmed]
  15. Structural characterization of a novel Cbl phosphotyrosine recognition motif in the APS family of adapter proteins. Hu, J., Hubbard, S.R. J. Biol. Chem. (2005) [Pubmed]
  16. Adaptor protein APS binds the NH2-terminal autoinhibitory domain of guanine nucleotide exchange factor Vav3 and augments its activity. Yabana, N., Shibuya, M. Oncogene (2002) [Pubmed]
  17. Molecular cloning of the mouse APS as a member of the Lnk family adaptor proteins. Iseki, M., Takaki, S., Takatsu, K. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  18. Identification of the APS protein as a novel insulin receptor substrate. Moodie, S.A., Alleman-Sposeto, J., Gustafson, T.A. J. Biol. Chem. (1999) [Pubmed]
  19. The adapter protein APS associates with the multifunctional docking sites Tyr-568 and Tyr-936 in c-Kit. Wollberg, P., Lennartsson, J., Gottfridsson, E., Yoshimura, A., Rönnstrand, L. Biochem. J. (2003) [Pubmed]
  20. APS, an adaptor molecule containing PH and SH2 domains, has a negative regulatory role in B cell proliferation. Iseki, M., Kubo-Akashi, C., Kwon, S.M., Yamaguchi, A., Takatsu, K., Takaki, S. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  21. The isolation and characterization of cDNA encoding the mouse bifunctional ATP sulfurylase-adenosine 5'-phosphosulfate kinase. Li, H., Deyrup, A., Mensch, J.R., Domowicz, M., Konstantinidis, A.K., Schwartz, N.B. J. Biol. Chem. (1995) [Pubmed]
  22. Reaction mechanism of the iron-sulfur flavoenzyme adenosine-5'-phosphosulfate reductase based on the structural characterization of different enzymatic states. Schiffer, A., Fritz, G., Kroneck, P.M., Ermler, U. Biochemistry (2006) [Pubmed]
  23. Large-scale sequencing of two regions in human chromosome 7q22: analysis of 650 kb of genomic sequence around the EPO and CUTL1 loci reveals 17 genes. Glöckner, G., Scherer, S., Schattevoy, R., Boright, A., Weber, J., Tsui, L.C., Rosenthal, A. Genome Res. (1998) [Pubmed]
  24. Signaling by Kit protein-tyrosine kinase--the stem cell factor receptor. Roskoski, R. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  25. Prediction of successful ablation site of concealed posteroseptal accessory pathways by a novel algorithm using baseline electrophysiological parameters: implication for an abbreviated ablation procedure. Chiang, C.E., Chen, S.A., Tai, C.T., Wu, T.J., Lee, S.H., Cheng, C.C., Chiou, C.W., Ueng, K.C., Wen, Z.C., Chang, M.S. Circulation (1996) [Pubmed]
  26. Plasma tumor necrosis factor alpha levels and the -238*A promoter polymorphism in patients with antiphospholipid syndrome. Bertolaccini, M.L., Atsumi, T., Lanchbury, J.S., Caliz, A.R., Katsumata, K., Vaughan, R.W., Kondeatis, E., Khamashta, M.A., Koike, T., Hughes, G.R. Thromb. Haemost. (2001) [Pubmed]
  27. Antibodies against hair follicles are associated with alopecia totalis in autoimmune polyendocrine syndrome type I. Hedstrand, H., Perheentupa, J., Ekwall, O., Gustafsson, J., Michaëlsson, G., Husebye, E., Rorsman, F., Kämpe, O. J. Invest. Dermatol. (1999) [Pubmed]
  28. Phylogenetic analysis reveals multiple lateral transfers of adenosine-5'-phosphosulfate reductase genes among sulfate-reducing microorganisms. Friedrich, M.W. J. Bacteriol. (2002) [Pubmed]
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