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)

The physician of an orphanage in Afgoye, 30 km from Mogadishu, Somalia, noticed vaginal discharge in 95 of the 500 girls at the orphanage in September 1987. A Somali-Italian investigative team took vaginal specimens from the 95 girls. Laboratory personnel isolated Neisseria gonorrhoea in 56% of the 95 6-14 year old females (53) who all lived in 2 adjacent dormitories. They found that all the bacterial isolates were of the N. gonorrhoea WI serogroup and Aedih serovar. The physician prescribed penicillin treatment for all the girls. Contact tracing revealed that a male guardian was the source of gonorrhea. Some children had already accused him of sexually abusing them. Orphanage officials had transferred him 1 week before the arrival of the investigative team. His room had been very near to the 2 dormitories for only a few weeks before the investigative team arrived. In this short time, his sexual abuse effected this cluster of infections. This supports the present theory of gonorrhea epidemiology that a core group of infectious people are most likely responsible for most, if not all, of the continuing endemicity of gonorrhea. The infection rate was in range of the estimated probability of transmission (50-70%) during sexual intercourse from an infectious male to a female. The results showed that high resolution typing of gonococci has in addition to its scientific value a more practical value; forensic medicine and illustration that gonorrhea consists of smaller microepidemics.
Int J STD AIDS
PMID:An epidemic of Neisseria gonorrhoeae in a Somali orphanage. 154 69

A 32-year-old male (Mr. A.), monitored during an 8-d heat acclimation (HA) investigation, unexpectedly exhibited heat intolerance and heat exhaustion. Thirteen other males completed HA without indications of either heat intolerance or heat exhaustion. Because Mr. A. responded normally to HA on days 1-4, the intervention of an unknown host factor on days 5-8 was suggested. Mr. A.'s heat exhaustion episode (day 8) was apparently forewarned by loss of body weight and increased delta HR, delta Tsk (days 5-8) and delta Tre (days 7-8) during daily 90-min trials. His symptoms indicated classical salt depletion heat exhaustion, but the calculated salt deficit (less than 0.1 g NaCl.kg-1 body weight) was mild. Post-heat exhaustion serum enzyme levels were either normal (ALT, AST) or acutely elevated (CPK). Blood beta-endorphin and cortisol levels were six times and two times greater than control values, respectively. This case report is unique because clinical/physiological measurements and blood analyses were performed before, during, and after heat intolerance and heat exhaustion.
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PMID:Heat intolerance, heat exhaustion monitored: a case report. 335 82

A lot of over 60 atherosclerotics with clinical manifestations of senile depressive illness was studied comparatively with a lot of subjects of the same age with essential arterial hypertension (EAH). As concerns the behaviour of the catecholamine content in CSF and blood, the total catecholamines are approxiately equal in the two lots, but with a clear difference of the catecholamine fractions. The CSF catecholamines behaviour in old atherosclerotics is characterized by the presence of increased values of noradrenaline (NA) and of adrenaline (A), with increased statistical significance, but without modifications of the adrenaline percentage (A %) from the total catecholamines, comparatively to the values found in normal subjects. The serotonin (5-HT) content of the CSF in men with atherosclerotic senile depressive illness was lower even than in subjects with coronary atherosclerosis. In atherosclerosis protides modifications precede the histologic changes. In CSF, GLU, ALA, TYR increase in old subjects. In blood, GLU, ALA, TYR, HIS, LEU, SER increase in the same subjects. ARG decreases with age. THR is higher in men than in women. In the urine of all the men as well as of all the women of more than 60 years, GLN and ALA have increased values. LYS increases with age. GLN and ARG are higher in men than in women.
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PMID:Pattern of the cerebrospinal fluid (CSF) and blood biogenic amines and of the CSF, blood and urine amino acids as pathogenetic ground of the senile depressive illness. 677 91

X-linked agammaglobulinaemia (XLA) is an inherited immunodeficiency resulting from mutations in the gene for a cytoplasmic protein tyrosine kinase (Btk). We have utilised reverse-transcription-based PCR in combination with the chemical cleavage and mismatch technique (CCM) to screen for Btk mutations in 42 unrelated patients having classical XLA or 'leaky' XLA-like phenotypes. A variety of mutations, including point mutations, large deletions and splicing defects were detected using this strategy. In total, 20 mutations were found in these patients. All the mutations were different with the exception of three unrelated patients who all showed the same Arg-->His amino acid substitution (R641H) at a highly-conserved residue in the kinase domain. We have also used structural modelling of the Btk kinase domain to predict how two different amino acid substitution mutations at highly-conserved residues are likely to affect the Btk kinase activity.
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PMID:Identification of Btk mutations in 20 unrelated patients with X-linked agammaglobulinaemia (XLA). 763 20

The genetic etiology of thyroid hormone resistance syndromes is now well established. Two clinical variants, generalized resistance to thyroid hormone (GRTH) and selective pituitary resistance to thyroid hormone (PRTH), are, in most cases, caused by heterozygous mutations in the ligand-binding domain of the c-erbA beta thyroid hormone receptor gene. No human mutations have yet been described in the other related receptor gene, c-erbA alpha. In resistant patients, the mutant beta receptors act as dominant negative proteins and inhibit function of the normal beta receptor (expressed from one allele) and the normal alpha receptor (expressed from two alleles). Patients homozygous for a dominant negative allele (the Bercu patient) and without any beta receptor (the Refetoff patient) have been described. Patients with GRTH and PRTH both present with elevated free thyroxine and triiodothyronine and inappropriately normal thyroid-stimulating hormone, but the former patients are clinically euthyroid, whereas the latter patients have symptoms and signs of hyperthyroidism. However, in some cases, different patients who have been classified as having GRTH and PRTH have been found to have identical beta mutations. A recent study of the level of pituitary resistance in a large kindred with GRTH (ARG-320-HIS mutation) indicated a contributory gene in the regulation of thyroid hormone action. Relative overexpression of the mutant PRO-453-HIS receptor at the level of messenger RNA in patient fibroblasts (kindred A) was associated with short stature. Finally, an ARG-316-HIS mutation (kindred G-H) was associated with relatively weak dominant negative activity and perturbed DNA-binding properties.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Resistance to thyroid hormone in children. 795 71

The Philadelphia chromosome, detected in virtually all cases of chronic myelogenous leukemia, is formed by a reciprocal translocation between chromosomes 9 and 22 that fuses BCR encoded sequences upstream of exon 2 of c-ABL. This oncogene produces a fusion protein, p210BCR-ABL, in which the ABL tyrosine kinase activity is elevated. This elevated kinase activity is essential for transformation, but the mechanisms involved are unknown. To investigate p210BCR-ABL function we constructed a model system in which the tyrosine kinase activity of p210BCR-ABL was inducible. Two amino acid substitutions, Arg to His at amino acid 457 and Tyr to His at amino acid 469 of c-abl, modeled on mutations known to render v-src temperature-sensitive for tyrosine kinase activity, were introduced into p210BCR-ABL. This mutant was characterized in an IL-3 growth factor dependent murine myeloid cell line, 32Dc13. Cell lines expressing the temperature-sensitive mutant remained factor dependent at the non-permissive temperature, but at the permissive temperature displayed a marked reduction in cell death in the absence of growth factor and an exaggerated proliferative response to low levels of IL-3. Both the kinase activity of the mutant and the levels of tyrosine phosphorylated proteins are increased in the temperature-sensitive mutant at the permissive temperature. Further, tyrosine phosphorylation of potential substrates of the p210BCR-ABL tyrosine kinase, p120 rasGAP and its associated proteins of p190 and p62, only occurs at the permissive temperature in cells expressing the temperature-sensitive mutant.
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PMID:Use of a temperature-sensitive mutant to define the biological effects of the p210BCR-ABL tyrosine kinase on proliferation of a factor-dependent murine myeloid cell line. 830 74

We have examined the c-erbA beta thyroid hormone receptor gene in a kindred, G.H., with a member, patient G.H., who had a severe form of selective pituitary resistance to thyroid hormones (PRTH). This patient manifested inappropriately normal thyrotropin-stimulating hormone, markedly elevated serum free thyroxine (T4) and total triiodothyronine (T3), and clinical hyperthyroidism. The complete c-erbA beta 1 coding sequence was examined by a combination of genomic and cDNA cloning for patient G.H. and her unaffected father. A single mutation, a guanine to adenine transition at nucleotide 1,232, was found in one allele of both these members, altering codon 311 from arginine to histidine. In addition, a half-sister of patient G.H. also harbored this mutant allele and, like the father, was clinically normal. The G.H. receptor, synthesized with reticulocyte lysate, had significantly defective T3-binding activity with a Ka of approximately 5 x 10(8) M-1. RNA phenotyping using leukocytes and fibroblasts demonstrated an equal level of expression of wild-type and mutant alleles in patient G.H. and her unaffected father. Finally, the G.H. receptor had no detectable dominant negative activity in a transfection assay. Thus, in contrast to the many other beta-receptor mutants responsible for the generalized form of thyroid hormone resistance, the G.H. receptor appeared unable to antagonize normal receptor function. These results suggest that the arginine at codon 311 in c-erbA beta is crucial for the structural integrity required for dominant negative function. The ARG-311-HIS mutation may contribute to PRTH in patient G.H. by inactivating a beta-receptor allele, but it cannot be the sole cause of the disease.
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PMID:An arginine to histidine mutation in codon 311 of the C-erbA beta gene results in a mutant thyroid hormone receptor that does not mediate a dominant negative phenotype. 838 21

In this study we describe an investigation into the residual spelling skills of a patient (BRK) with a deep dysgraphia. His written spelling was significantly superior to his oral spelling and he had grave difficulties in recognizing orally spelled words. In addition, his impairment in recognizing orally spelled words was qualitatively very similar to his difficulties in oral spelling. In contrast, he could read and repeat the stimuli he could no longer spell. It seems therefore that, recognizing orally spelled words is dependent on the same procedures used in spelling rather than in reading. It is argued that BRK's discrepancy between oral and written spelling reflects a deficit in accessing a letter name code which translates abstract graphemic representations into letter names. In addition, it is suggested that the letter name code has an additional synthesizing function that is involved both in checking self-generated oral spellings and in recognizing orally spelled words.
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PMID:Does recognizing orally spelled words depend on reading? An investigation into a case of better written than oral spelling. 914 99

Focal adhesion kinase (FAK) has been overexpressed in insect cells using a baculovirus expression system. A recombinant baculovirus was generated which contains the mouse FAK cDNA cloned into a histidine tag transfer vector. Synthesis of the immunoreactive recombinant protein (baculovirus focal adhesion kinase (BFAK) Mr approximately 125,000) in infected Sf9 cells was detected 23 h postinfection, with maximal accumulation occurring at 48 h postinfection. BFAK constituted 5.4% of total soluble protein in the insect cell lysate and represented 19 mg/liter culture (approximately 2 x 10(9) cells). The enzyme was active as a protein tyrosine kinase in both SF9 cells and in vitro. Purification to near homogeneity was achieved by nickel chelation chromatography. A yield of 5 mg of purified active BFAK was consistently produced from 1 liter of infected insect cells. BFAK tyrosine kinase activity was characterized physically using poly(Glu-Tyr) as a substrate. BFAK activity required the presence of a divalent cation and exhibited a preference for Mn2+ over Mg2+. Maximal tyrosine kinase activity was attained at pH 7.2. Steady-state kinetic analysis with respect to ATP concentration did not conform to simple Michaelis-Menten kinetics and exhibited a Hill coefficient of much less than 1. Km values for ATP using native and autophosphorylated BFAK were 6.7 +/- 1.0 and 4.3 +/- 0.2 microM, respectively. Kcat values were 13.9 +/- 1.9 and 8.9 +/- 0.3 nmol/min/mg BFAK. Steady-state kinetics with respect to the peptide substrate did fit the Michaelis-Menten equation and exhibited a Km value of 2.4 +/- 0.3 micro/ml.
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PMID:Expression, purification and characterization of focal adhesion kinase using a baculovirus system. 917 76

Cell adhesive interactions play important roles during many normal physiological processes such as embryonic development and wound repair, and also during the progression of diseases such as cancer. Cell adhesion is mediated by the specific interactions of cell surface receptors with extracellular glycoproteins. The best characterized cell adhesion receptors are the integrins. Integrins comprise a family of more than 23 noncovalent, heterodimeric complexes consisting of an alpha and a beta subunit. Each subunit is a glycoprotein with a large, globular extracellular domain and a transmembrane domain. Most integrins have relatively small cytoplasmic domains consisting of fewer than 60 amino acids. Although many integrins can bind fibronectin, the alpha 5, beta 1, integrin is the major fibronectin receptor on most cells. This integrin mediates such cellular responses to fibronectin substrates as adhesion, migration, assembly of extracellular matrix, and signal transduction. Integrin ligands, such as fibronectin, are not passive adhesive molecules but are active participants in the cell adhesive process that leads to signal transduction. The best characterized integrin ligand is fibronectin. Fibronectin is a multifunctional glycoprotein comprised of three different types of homologous repeating units (termed type I, type II, and type III). Fibronectin has at least two independent cell adhesive regions: one located near the center of the polypeptide chain in the ninth and tenth type III modules binds to the alpha 5 beta 1 integrin. The biological function of the central cell adhesive region requires two critical amino acid sequences--an Arg-Gly-Asp (RGD) sequence and a Pro-His-Ser-Arg-Asn (PHSRN) sequence, which function in synergy--for optimal binding to the alpha 5 beta 1 integrin. Furthermore, the spacing between the crucial RGD and PHSRN sequences is also important for activity, suggesting the sequences themselves are necessary, but not sufficient, to account for the cell adhesive activity of fibronectin. One of the manifestations of integrin-mediated signal transduction including protein tyrosine phosphorylation. One cytoplasmic protein that is phosphorylated in response to cell adhesion is the focal adhesion kinase known as pp125FAK or FAK. The beta 1, beta 3, and beta 5 integrin intracellular domains are sufficient to initiate signal transduction pathways. Furthermore, alternative splicing can regulate the ability of beta integrin intracellular domains to participate in signal transduction. Other intracellular responses to cell adhesion include stimulation of migration, the assembly of an F-actin cytoskeleton and specialized structures called focal contacts, changes of cytoplasmic pH and calcium ion concentration, and modulation of proliferation and gene expression. Such varied modes of signal transduction are probably differentially controlled by a mechanism that requires either integrin receptor clustering alone, ligand occupancy in addition to clustering, or clustering and/or ligand occupancy plus tyrosine kinase activity for different responses. The examination of the fundamental mechanisms important for adhesion of cultured human cells and the resultant signaling processes has the potential of providing an understanding of molecular mechanisms involved in complex physiological processes and serving the basis for the development of novel therapeutic agents for the treatment of human disease.
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PMID:Integrins in cell adhesion and signaling. 918 47


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