Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An angle Omega is defined to serve as a metric for global side-chain orientations, which reflects the orientation of the side chain relative to the radial vector from the center of the protein to an amino acid. The side-chain orientations of buried residues exhibit characteristically different orientations than do exposed residues, in both monomeric and dimeric structures. Overall, buried side chains point mostly inward, whereas surface side chains tend to point outward from the surface. This difference in behavior also correlates well with the residue hydrophobicity; so a global side-chain orientation can be viewed as a direct structural manifestation of hydrophobicity. When various solvent-accessible layers are considered, the behavior is relatively continuous between centrally located and exposed residues. In the case of interfacial residues between subunits, there are statistically significant differences between exposed residues and interface residues for ALA, ARG, ASN, ASP, GLU, HIS, LYS, THR, VAL, MET, PRO, and overall the interface residues have an increased tendency to point inward. Presumably, these substantial differences in orientations of side chains may be a manifestation of hydrophobic forces.
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PMID:How do side chains orient globally in protein structures? 1615 44

The first possibly causative molecular aberration in patients with myeloproliferative disorders has recently been described. A point mutation in the Janus kinase 2 exchanging a valine for a phenylalanine at position 617 (JAK2 V617F) was found in 65% to 97% of polycythemia vera (PV) patients, as well as in approximately 50% of essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF) patients. In addition, a growing set of molecular and genetic markers, some possibly contributing to disease development, some more likely epiphenomena, has been characterized in these patients over the last few years. Compiling and synthesizing the increasing knowledge on the genetic changes observed in myeloproliferative disorder (MPD) patients will allow us to generate testable hypotheses on the molecular etiology of disease development. Therefore, this review will summarize the current knowledge on chromosomal aberrations, molecular markers, and gene expression studies in MPD patients. From these data, a model depicting our current understanding of the interplay between these markers is presented.
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PMID:Chromosomal abnormalities and molecular markers in myeloproliferative disorders. 1621 33

Protein tyrosine kinases (PTKs) and phosphatases (PTPs) play a crucial role in normal cell development, and dysfunction of these enzymes has been implicated in human cancers. Polycythemia vera (PV) is a clonal hematologic disease characterized by hypersensitivity of hematopoietic progenitor cells to growth factors and cytokines. Recently, a unique and clonal mutation in the JAK homology 2 (JH2) domain of JAK2 that results in a valine to phenylalanine substitution at position 617 (V617F) was found in the majority of PV patients. This mutation leads to constitutive JAK2 activation and abnormal signaling and induces erythrocytosis in an animal model. The mutation is also found in a significant percentage of patients with idiopathic myelofibrosis (50%) and essential thrombocythemia (30%). Thus, it seems probable that this mutation associates with other molecular genetic events to cause different myeloproliferative disorders (MPDs). One of these secondary events is the transition to homozygosity of the mutated gene in 30% of the PV patients. Other events may include defects in PTPs, but these remain to be characterized. Recent studies represent a great step forward in the molecular pathogenesis in PV and the development of targeted new drugs to treat the disease.
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PMID:Role of tyrosine kinases and phosphatases in polycythemia vera. 1621 35

The discovery this year of a single mutation in the Janus Kinase (JAK)-2 gene in a high percentage of cases of polycythaemia vera (PV), essential thrombocythaemia (ET) and myelofibrosis suggests that it maybe the underlying molecular mechanism for these disorders. Different approaches from the inhibition of the tyrosine kinase JAK2, widespread search for mutations in tyrosine kinases, and investigation of the short arm of chromosome 9 where JAK2 is located all led to the discovery of the V617F JAK2 mutation. Substitution of a valine for a phenylalanine destabilizes the JH2 domain of JAK2 causes loss of the auto-inhibitory activity of this domain and explains some of the biological phenomena observed in patients with myeloproliferative disorders (MPD). The V617F JAK2 mutation can be detected by PCR-direct sequencing using DNA from the granulocyte lineage or with increased sensitivity by the amplification refractory mutation system using DNA from unfractionated blood. Pyrosequencing assays can be used to quantitate allele ratios to accurately define homozygote and heterozygote status. This single mutation is widespread having been detected in related MPD and other haematological malignancies. This leads to a number of further questions about the role of this single mutation in the clinical pattern of disease.
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PMID:The V617F JAK2 mutation and the myeloproliferative disorders. 1628 6

ZnS nanocrystal, a class of wide-gap semiconductors, has shown interesting optical, electrical, and optoelectric properties via quantum confinement. For those applications, phase controls of ZnS nanocrystals and nanowires were critical to tune their physical properties to the appropriate ones. The wurtzite ZnS nanocrystal growth at room temperature is the useful fabrication; however, the most stable ZnS structure in nanoscale is the zinc blende (cubic) structure, and scientists have just begun exploring the room-temperature synthesis of the wurtzite (hexagonal) structure of ZnS nanocrystals. In this report, we applied the Zn finger-like peptides as templates to control the phase of ZnS nanocrystals to the wurtzite structure at room temperature. The peptide nanotubes, consisting of a 20 amino acids (VAL-CYS-ALA-THR-CYS-GLU-GLN-ILE-ALA-ASP-SER-GLN-HIS-ARG-SER-HIS-ARG-GLN-MET-VAL, M1 peptide) synthesized based on the peptide motif of the Influenza Virus Matrix Protein M1, could grow the wurtzite ZnS nanocrystals on the nanotube templates in solution. In the M1 protein, the unfolding process of the helical peptide motif via pH change creates a linker region between N- and C-terminated helical domains that contains a Zn finger-like Cys2His2 motif. Because the higher pH increases the uptake of Zn ions in the Cys2His2 motif of the M1 peptide by unfolding more helical domains, the pH change can essentially control the size and the number of the nucleation sites in the M1 peptides to grow ZnS nanocrystals with desired phases. Here we optimized the nucleation sites in the M1 peptides by unfolding them via pH change to obtain highly monodisperse and crystalline wurtzite ZnS nanocrystals on the template nanotubes at room temperature. This type of peptide-induced biomineralization technique will provide a clean and reproducible method to produce semiconductor nanotubes due to its efficient nanocrystal formation, and the band gaps of resulting nanotubes can also be tuned simply by phase control of ZnS nanocrystal coatings via the optimization of the unfolding peptide structures.
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PMID:Room-temperature Wurtzite ZnS nanocrystal growth on Zn finger-like peptide nanotubes by controlling their unfolding peptide structures. 1628 68

Polycythaemia vera is an acquired myeloproliferative disorder characterised by a polycythaemia resulting of a clonal disorder arising in a multipotent hematopoietic stem cell. The increase of red cell mass exposes to a high risk of arterial or venous thrombosis and thus requires a cytoreductive treatment. An acquired genetic mutation in exon 12 of the JAK2 tyrosine kinase gene, leading to a substitution of a valine to a phenylalanine (V617F), has been described in most polycythaemia vera patients. This mutation increases the phosphorylation activity of JAK2, promotes the spontaneous cellular growth and induces erythrocytosis in a mouse model. Prevalence studies of V617F JAK2 mutation in different myeloproliferative disorders have found this genetic alteration in half of idiopathic myelofibrosis and in one third of essential thrombocythaemia. This finding is a huge progress in the understanding of polycythaemia vera physiopathology, it will be also an useful tool for the diagnosis of myeloproliferative disorders and it opens a new field for the development of targeted therapeutic approaches in these disorders.
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PMID:[Acquired mutation of JAK2 tyrosine kinase and polycythaemia vera]. 1642 Sep 86

Although a large proportion of patients with polycythemia vera (PV) harbor a valine-to-phenylalanine mutation at amino acid 617 (V617F) in the JAK2 signaling molecule, the stage of hematopoiesis at which the mutation arises is unknown. Here we isolated and characterized hematopoietic stem cells (HSC) and myeloid progenitors from 16 PV patient samples and 14 normal individuals, testing whether the JAK2 mutation could be found at the level of stem or progenitor cells and whether the JAK2 V617F-positive cells had altered differentiation potential. In all PV samples analyzed, there were increased numbers of cells with a HSC phenotype (CD34+CD38-CD90+Lin-) compared with normal samples. Hematopoietic progenitor assays demonstrated that the differentiation potential of PV was already skewed toward the erythroid lineage at the HSC level. The JAK2 V617F mutation was detectable within HSC and their progeny in PV. Moreover, the aberrant erythroid potential of PV HSC was potently inhibited with a JAK2 inhibitor, AG490.
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PMID:The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation. 1660 27

To identify transforming genes in acute myeloid leukemia (AML) we here constructed a retroviral cDNA expression library from an AML patient, and then used this library to infect a mouse cell line 32Dcl3-mCAT. cDNA inserts of the cell clones which proliferated in the presence of granulocyte colony-stimulating factor were derived from JAK3 encoding a JAK3 mutant with a valine-to-alanine substitution at codon 674 and two additional amino acid substitutions. The transforming activity of JAK3(V674A) was confirmed by its introduction into 32Dcl3-mCAT. Sequencing of the original JAK3 cDNA derived from the patient, however, failed to detect the V674A mutation.
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PMID:Identification of a constitutively active mutant of JAK3 by retroviral expression screening. 1679 Feb 75

A point mutation in the JAK2 gene, a member of the tyrosine kinase family, was recently identified and shown to be associated with several myeloproliferative disorders. Several studies identified the same JAK2 point mutation (1,849G>T), resulting in the substitution of a valine to phenylalanine at codon 617 (V617F). We developed a simple and sensitive method to detect this mutation via polymerase chain reaction and probe dissociation analysis using the LightCycler platform, and we compared this method to existing restriction fragment-length polymorphism, direct sequencing, and amplification refractory mutation system methods. We found that the LightCycler method offered advantages of speed, reliability, and more straightforward interpretation over the restriction fragment-length polymorphism and sequencing approaches.
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PMID:Detection of the JAK2 V617F mutation by LightCycler PCR and probe dissociation analysis. 1682 5

The Philadelphia-negative chronic myeloproliferative disorders feature autonomous myeloid hyperproliferation and hypersensitivity to a number of growth factors, which most recently have been shown to be explained by a guanine-to-thymidine mutation in the Janus tyrosine kinase (JAK2) gene, implicating that phenylalanine is substituted with valine in position 617 (V617F mutation). JAK2 is of particular importance to haematopoiesis, since JAK2 proteins are activated mainly by the haematopoietic growth factors. The JAK2 mutation is present in most patients with polycythaemia vera and about 50% of patients with essential thrombocytosis and idiopathic myelofibrosis. The identification of the JAK2 mutation is a major molecular breakthrough in the understanding of the pathobiology of these disorders, and it is a new molecular marker to be used in the future classification of the diseases as well as a simple and rapid diagnostic test. The mutated JAK2 tyrosine kinase is an obvious potential target for a small-molecule inhibitor of tyrosine kinase activity.
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PMID:[New molecular markers within the chronic myeloproliferative disorders. II: the JAK2 mutation]. 1703 92


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