Disease relevance of GRAP2

• Here, we show that Grap-2 is also expressed in neuroendocrine tumors and cell lines known to bear mutated forms of RET [1].
• We report the identification of a new simian immunodeficiency virus (SIV), designated SIVden, in a naturally infected Dent's Mona monkey (Cercopithecus mona denti), which was kept as pet in Kinshasa, capital of the Democratic Republic of Congo [2].
• P38 MAP kinase mediates transforming growth factor-beta2 transcription in human keloid fibroblasts [3].
• The DNA encoding the C-terminal SH3 domain of GADS (GADS-cSH3) was assembled synthetically using a recursive PCR technique and the protein was overexpressed in Escherichia coli, refolded and purified [4].
• In Borrelia burgdorferi B31MI, class I includes the outer surface protein E (OspE) paralogs, L39, N38, and P38, whereas the class II group includes A68 and additional proteins that have not yet been identified [5].

Psychiatry related information on GRAP2

• The Illness Self-Concept Repertory Grid appears capable of predicting treatment outcome and shows promise as a prognostic tool [6].
• P38 MAP kinase is activated at early stages in Alzheimer's disease brain [7].
• OBJECTIVE: This study investigated the psychometric properties of the Threshold Assessment Grid (TAG), a new assessment of the severity of mental health problems [8].
• Seventy-six healthy women (29 users and 47 nonusers; 18 to 48 years old), completed the State-Trait Anger Expression Inventory, the Clinical Analysis Questionnaire, the Rotter Scale of locus of control, the Daily Hassles Scale, and a Repertory Grid [9].
• The assessments included Cattell's 16PF Personality Inventory, a Body-Esteem index, a computer administered version of the Repertory Grid technique and semi-structured interviews [10].

High impact information on GRAP2

• These results suggest that the conformational state of P38, controlled by Fpr4, is important for methylation of H3K36 by Set2 [11].
• The mammalian growth factor receptor-binding protein Grb2 is an adaptor that mediates activation of guanine nucleotide exchange on Ras [12].
• RAC1/P38 MAPK signaling pathway controls beta1 integrin-induced interleukin-8 production in human natural killer cells [13].
• The SLP-76 peptide engages four distinct binding pockets on the surface of the Gads SH3 domain and upon binding adopts a unique structure characterized by a right-handed 3(10) helix at the RSTK locus, in contrast to the left-handed polyproline type II helix formed by canonical proline-rich SH3 ligands [14].
• The Gads function was able to be replaced by overexpression of Grb2 [15].

Chemical compound and disease context of GRAP2

• CONCLUSION: (1) Both DTT and cisplatin were able to induce apoptosis in esophageal cancer cell line Eca109; (2) P38 MAP kinase is essential for DTT- and cisplatin-induced apoptosis in Eca109 cells; (3) P38 activation may be the common signaling component relaying the multiple upstream signaling events to the downstream cell death program [16].
• AIM: To study the role of P38 kinase in esophageal cancer cell apoptosis induced by genotoxin, cisplatin and the unfolded protein response (UPR) inducer, dithiothreitol (DTT) [16].
• P38 MAPK, but not p42/p44 MAPK mediated inducible nitric oxide synthase expression in C6 glioma cells [17].

Biological context of GRAP2

• Gads contains a Src homology 2 (SH2) domain, which has previously been shown to have a similar binding specificity to that of Grb2 [18].
• We first confirmed that the -2000 to +150 genomic region relative to the Mona gene transcription start site is sufficient to direct specific reporter gene expression in T cell lines, Jurkat, and MOLT-4 and in the immature myeloid cell lines, KG1a and RC2A [19].
• We report here that 1B mRNA expressing cells do not express detectable amounts of Mona protein, in contrast to 1A expressing cells, and we show that 1B 5'UTR contains upstream open reading frames (uORFs) [20].
• Strikingly, platelet activation by thrombin resulted in the rapid induction of Mona protein expression, suggesting that translation inhibition of 1B mRNA may be relieved in activated platelets [20].
• Grap-2, a novel RET binding protein, is involved in RET mitogenic signaling [1].

Anatomical context of GRAP2

• Expression of Grf40 is predominant in hematopoietic cells, particularly T cells [21].
• Grf40 binds to the SH2 domain-containing leukocyte protein of 76 kD (SLP-76) via its SH3 domain more tightly than Grb2 [21].
• Gads protein expression is restricted to hematopoietic tissues and cell lines [18].
• Gads is most highly expressed in the thymus and spleen of adult animals and in human leukemic cell lines [22].
• Grap2 is a newly identified adaptor protein specifically expressed in lymphoid tissues [23].

Associations of GRAP2 with chemical compounds

• Taken together, these results suggest that besides being involved in tyrosine kinase signaling in hematopoietic cells, Grap-2 plays a tissue-specific role as an inhibitor of RET mitogenic signaling [1].
• Evidence for the requirement of ITAM domains but not SLP-76/Gads interaction for integrin signaling in hematopoietic cells [24].
• Here we studied the functional roles of sub-domains within the SLP-76 proline-rich region, specifically the Gads binding domain and the recently defined P1 domain [25].
• Furthermore, siRNA against DDR1 significantly inhibited bleomycin-induced P38 MAPK activation in the lungs [26].
• However, the Grap2 protein has a unique 120-amino acid glutamine- and proline-rich domain between the SH2 and C-terminal SH3 domains [23].

Physical interactions of GRAP2

• We found that GCIP bound to Grap2 in both yeast two-hybrid assays and in mammalian cells through binding to the COOH-terminal unique domain and SH3 domain (designated QC domain) of Grap2 [27].
• Incidentally, Grf40 binds to linker for activation of T cells (LAT) possibly via its SH2 domain [21].
• We found that Grap2 interacted with the hematopoietic progenitor kinase 1 (HPK1) in vitro and in Jurkat T cells [23].

Enzymatic interactions of GRAP2

• Gads also coimmunoprecipitated the tyrosine-phosphorylated form of the linker for activated T cells (LAT) adaptor protein following cross-linking of the T-cell receptor; this interaction was mediated by the Gads SH2 domain [18].

Regulatory relationships of GRAP2

• RESULTS: We found that Gads is highly expressed in T cells and that the SLP-76 adaptor protein is a major Gads-associated protein in vivo [18].
• Vascular endothelial growth factor is upregulated by interleukin-1 beta in human vascular smooth muscle cells via the P38 mitogen-activated protein kinase pathway [28].
• Gads is a member of the family of SH2 and SH3 domain containing adaptor proteins that is expressed specifically in hematopoietic cells and functions in the coordination of tyrosine kinase mediated signal transduction [29].

Other interactions of GRAP2

• Using Grap2 as bait protein, we identified a novel human protein, GCIP (Grap2 cyclin-D interacting protein) [27].
• Characterization of promoter elements directing Mona/Gads molecular adapter expression in T and myelomonocytic cells: involvement of the AML-1 transcription factor [19].
• We molecularly cloned a new Grb2 family member, named Grf40, containing the common SH3-SH2-SH3 motif [21].
• Mona, also called Gads, is a molecular adapter that plays a key role in T-cell and platelet signalling by linking the adaptors Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa (Slp-76) and linker for activation of T cells (LAT) upon T-cell receptor and collagen receptor activation [20].
• BACKGROUND: The adaptor protein Gads is a Grb2-related protein originally identified on the basis of its interaction with the tyrosine-phosphorylated form of the docking protein Shc [18].

Analytical, diagnostic and therapeutic context of GRAP2

• Molecular cloning and expression of human grap-2, a novel leukocyte-specific SH2- and SH3-containing adaptor-like protein that binds to gab-1 [30].
• Furthermore, Northern blot analysis demonstrated that Grap-2 has two major transcripts of 1.4 and 4.0 kb that can only be detected in tissues rich in leukocytes and in two leukemia cell lines [30].
• Sequence analysis revealed that Grap-2 contains a SH3-SH2-SH3 structure that has a high degree of sequence homology to those of the Grb-2 and Grap adaptor molecules [30].
• Activation of the JNK1 and P38 kinase cascades and their potential targets was detected by Western blot analysis [31].
• RESULTS: P38 and JNK1 and their respective upstream activating kinases, MKK3/6 and -4, were all transiently activated in FCS-stimulated RPE cell cultures [31].

References