Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Signal transduction through the T-cell receptor and cytokine receptors on the surface of T lymphocytes occurs largely via tyrosine phosphorylation of intracellular substrates. Because neither the T-cell receptor nor cytokine receptors contain intrinsic kinase domains, signal transduction is thought to occur via association of these receptors with intracellular protein tyrosine kinases. Although several members of the SRC and SYK families of tyrosine kinases have been implicated in signal transduction in lymphocytes, it seems likely that additional tyrosine kinases involved in signal transduction remain to be identified. To identify unique T-cell tyrosine kinases, we used polymerase chain reaction-based cloning with degenerate oligonucleotides directed at highly conserved motifs of tyrosine kinase domains. We have cloned the complete cDNA for a unique human tyrosine kinase that is expressed mainly in T lymphocytes (EMT) and natural killer (NK) cells. The cDNA of EMT predicts an open reading frame of 1866 bp encoding a protein with a predicted size of 72 Kd, which is in keeping with its size on Western blotting. A single 6.2-kb EMT mRNA and 72-Kd protein were detected in T lymphocytes and NK-like cell lines, but were not detected in other cell lineages. EMT contains both SH2 and SH3 domains, as do many other intracellular kinases. EMT does not contain the N-terminal myristylation site or the negative regulatory tyrosine phosphorylation site in its carboxyterminus that are found in the SRC family of tyrosine kinases. EMT is related to the B-cell progenitor kinase (BPK), which has recently been implicated in X-linked hypogammaglobulinemia, to the TECI mammalian kinase, which has been implicated in liver neoplasia, to the more widely expressed TECII mammalian kinase, and to the Drosophila melanogaster Dsrc28 kinase. Sequence comparison suggests that EMT is likely the human homologue of a recently identified murine interleukin-2 (IL-2)-inducible T cell kinase (ITK). However, unlike ITK, EMT message and protein levels do not vary markedly on stimulation of human IL-2-responsive T cells with IL-2. Taken together, it seems that EMT is a member of a new family of intracellular kinases that includes BPK, TECI, and TECII. EMT was localized to chromosome 5q31-32, a region that contains the genes for several growth factors and receptors as well as early activation genes, particularly those involved in the hematopoietic system. Furthermore, the 5q31-32 region is implicated in the genesis of the 5q- syndrome associated with myelodysplasia and development of leukemia.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Identification, cloning, and characterization of a novel human T-cell-specific tyrosine kinase located at the hematopoietin complex on chromosome 5q. 836 6

JAK2 V617F mutation is mostly seen in BCR-ABLI negative myeloproliferative neoplasms. Among other myeloid neoplasms, it occurs with remarkably high frequency in refractory anemia with ring sideroblasts associated with marked thrombocytosis, a group of myeloid neoplasms with both dysplastic and proliferative features. It has also been reported in occasional cases of myelodysplastic syndrome with isolated del(5q), often with a diagnosis of refractory cytopenia with multilineage dysplasia. We performed a retrospective analysis of JAK2 V617F mutation in Chinese patients with myeloid neoplasms and isolated del(5q), and were able to demonstrate the frequent occurrence of JAK2 V617F mutation in 5q- syndrome.
 ...
PMID:JAK2 V617F mutation is associated with 5q- syndrome in Chinese. 1956 18

During the past few years our understanding of the genetic basis for the myelodysplastic syndromes (MDS) has improved significantly. A few subgroups have been studied in detail and the genetic alterations are now to a great extent revealed. In 5q- syndrome haploinsufficiency of the ribosomal gene RPS14 appears to cooperate with loss of two micro-RNAs miR-145 and miR-146 to induce key features of the disease. Some mutations are specific for certain categories of MDS while others, such as TET2 seem to occur across the various categories. JAK2 mutations are mainly found in patients with myeloproliferative characteristics. The prognostic implications of most of the novel mutations are not yet fully understood, moreover, functional studies are required in order to understand the interplay between the different lesions; how they give rise to the disease and how some may lead to disease evolution including leukemic transformation. An improved understanding of the pathophysiology of MDS may lead to the identification of suitable targets for future drug development.
 ...
PMID:New clues to the molecular pathogenesis of myelodysplastic syndromes. 2021 Nov 65

A 66-year-old man who presented with progressive and marked thrombocytosis but normal hemoglobin was diagnosed to have essential thrombocythemia upon the demonstration of JAK2 V617F mutation. Bone marrow examination, however, showed the presence of monolobulated megakaryocytes and conventional cytogenetic analysis revealed an isolated interstitial deletion of the long arm of chromosome 5, characteristic of 5q- syndrome. A literature review indicated that isolated deletion of 5q is uncommon in essential thrombocythemia but that, when this isolated deletion is present, the disease often shows mixed features of both essential thrombocythemia and 5q- syndrome.
 ...
PMID:Essential thrombocythemia with deleted 5q--a genetic and morphologic hybrid? 2063 67

Interstitial deletion of chromosome 5q is the most common chromosomal abnormality in myelodysplastic syndromes. The catalogue of genes involved in the molecular pathogenesis of myelodysplastic syndromes is rapidly expanding and next-generation sequencing technology allows detection of these mutations at great depth. Here we describe the design, validation and application of a targeted next-generation sequencing approach to simultaneously screen 25 genes mutated in myeloid malignancies. We used this method alongside single nucleotide polymorphism-array technology to characterize the mutational and cytogenetic profile of 43 cases of early or advanced del(5q) myelodysplastic syndromes. A total of 29 mutations were detected in our cohort. Overall, 45% of early and 66.7% of advanced cases had at least one mutation. Genes with the highest mutation frequency among advanced cases were TP53 and ASXL1 (25% of patients each). These showed a lower mutation frequency in cases of 5q- syndrome (4.5% and 13.6%, respectively), suggesting a role in disease progression in del(5q) myelodysplastic syndromes. Fifty-two percent of mutations identified were in genes involved in epigenetic regulation (ASXL1, TET2, DNMT3A and JAK2). Six mutations had allele frequencies <20%, likely below the detection limit of traditional sequencing methods. Genomic array data showed that cases of advanced del(5q) myelodysplastic syndrome had a complex background of cytogenetic aberrations, often encompassing genes involved in myeloid disorders. Our study is the first to investigate the molecular pathogenesis of early and advanced del(5q) myelodysplastic syndromes using next-generation sequencing technology on a large panel of genes frequently mutated in myeloid malignancies, further illuminating the molecular landscape of del(5q) myelodysplastic syndromes.
...
PMID:Targeted re-sequencing analysis of 25 genes commonly mutated in myeloid disorders in del(5q) myelodysplastic syndromes. 2383 21

Recent studies have greatly illuminated the genomic landscape of the myelodysplastic syndromes (MDS), and the pace of discovery is accelerating. The most common mutations found in MDS occur in genes involved in RNA splicing (including SF3B1, SRSF2, U2AF1, and ZRSR2) and epigenetic modification (including TET2, ASXL1, and DNMT3A). The identification of spliceosome mutations in approximately half of all patients with MDS implicates abnormalities of RNA splicing, a pathway not previously known as a target for mutation, in the MDS pathogenesis. Several regulators of signal transduction (NRAS, JAK2) and transcription factors (RUNX1, TP53) are also frequently mutated in MDS. The complex patterns of associations between gene mutations identified have revealed epistatic interactions between spliceosome components and epigenetic modifiers in MDS. The cytogenetic abnormalities found in MDS are characterized by the loss of genetic material, whereas translocations are rare. The cytogenetic deletion maps of MDS (e.g., 5q-, 7q-, 20q-) provide us with circumstantial evidence for the presence of tumor suppressor genes. It is now recognized that haploinsufficiency (a gene dosage effect) resulting from gene deletions or inactivating mutations is an important disease mechanism in MDS. Haploinsufficiency of the ribosomal protein gene RPS14 plays a critical role in the development of anemia in the 5q- syndrome, and haploinsufficiency of CUX1 is important in some patients with MDS and AML with complete or partial loss of chromosome 7. Gene expression profiling has identified key deregulated genes and pathways and new prognostic gene signatures in MDS. Recent advances in the molecular pathogenesis of MDS are leading to new biological, clinical, and therapeutic insights.
...
PMID:The molecular pathogenesis of the myelodysplastic syndromes. 2564 50