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

• Energy intake, energy expenditure, fat content, body weight, and plasma insulin, leptin, glucose, and lipid levels were similar between APS(-/-) and WT littermates fed either normal chow or a high-fat diet [10].
• The antimalarial drug hydroxychloroquine (HQ) has been used successfully in prevention of postoperative thrombosis and in treatment of patients with SLE or APS [5].
• Sulfite was oxidized in the Arthrobacter species by APS reductase and sulfite dehydrogenase [11].
• APS may be important due to their binding specificity to phosphatidylserine molecules which become accessible during apoptosis; this in turn may lead to local thrombosis [12].
• The reaction mechanism of adenosine 5'-phosphosulfate (APS) reductase (EC 1.8.99.2) from Thiobacillus thioparus was studied using difference spectrum and stopped-flow techniques [13].

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

• In vitro binding experiments suggest that APS bound to the beta type PDGF receptor, mainly via phosphotyrosine 1021 (pY1021) [2].

Regulatory relationships of SH2B2

• PDGF induced phosphorylation of the tyrosine residue of APS close to the C-terminal end [2].

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].

References