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)

The purpose of this study was to monitor current and predict future rates of inbreeding in the Danish dairy breeds. Calves born from 1999 until 2003 and registered as Danish Holstein (1,883,983), Danish Jersey (336,966), or Danish Red (261,047) were reference populations. Average complete generation equivalent was approximately 7. For calves born in 2003, average inbreeding was 3.9, 3.4, and 1.4% for Holstein, Jersey, and Danish Red, respectively. In recent years, effective population sizes were 49, 53, and 47, respectively. Based on coancestry statistics, future effective population sizes will be 43, 42, and 51, respectively. The effective number of founders, effective number of ancestors, and effective number of founder genomes were calculated. These measures of genetic diversity were all low for Holstein and Jersey and somewhat larger for Danish Red. The most important ancestors of Danish Holstein were Elevation (13.8%), Chief (10.9%), and Bell (8.5%). The most important ancestor of Danish Red was Momentum (9.4%), a Red Holstein-Friesian. The most important ancestor for Danish Jersey was FYN Lemvig (12.1%) with a large number of progeny in the reference population. The results of this study indicate the necessity for active management of the rate of inbreeding in the future.
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PMID:Inbreeding in Danish dairy cattle breeds. 1582 80

SRC family kinases (SFKs) function in initiating Ca2+ release at fertilization in several species in the vertebrate evolutionary line, but whether they play a similar role in mammalian fertilization has been uncertain. We investigated this question by first determining which SFK proteins are expressed in mouse eggs, and then measuring Ca2+ release at fertilization in the presence of dominant negative inhibitors. FYN and YES proteins were found in mouse eggs, but other SFKs were not detected; based on this, we injected mouse eggs with a mixture of FYN and YES Src homology 2 (SH2) domains. These SH2 domains were effective inhibitors of Ca2+ release at fertilization in starfish eggs, but did not inhibit Ca2+ release at fertilization in mouse eggs. Thus the mechanism by which sperm initiate Ca2+ release in mouse eggs does not depend on SH2 domain-mediated activation of an SFK. We also tested the small molecule SFK inhibitor SU6656, and found that it became compartmentalized in the egg cytoplasm, thus suggesting caution in the use of this inhibitor. Our findings indicate that although the initiation of Ca2+ release at fertilization of mammalian eggs occurs by a pathway that has many similarities to that in evolutionarily earlier animal groups, the requirement for SH2 domain-mediated activation of an SFK is not conserved.
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PMID:SH2 domain-mediated activation of an SRC family kinase is not required to initiate Ca2+ release at fertilization in mouse eggs. 1585 19

Src family kinases are involved in transducing growth factor signals for cellular differentiation and proliferation in a variety of cell types. The activity of all Src family kinases (SFKs) is controlled by phosphorylation at their C-terminal 527-tyrosine residue by C-terminal SRC kinase, CSK. There is a paucity of information regarding the role of CSK and/or specific Src family kinases in neuronal differentiation. Pretreatment of PC12 cells with the Src family kinase inhibitor, PP1, blocked NGF-induced activation of SFKs and obliterated neurite outgrowth. To confirm a role for CSK and specific isoforms of SFKs in neuronal differentiation, we overexpressed active and catalytically dead CSK in the rat pheochromocytoma cell line, PC12. CSK overexpression caused a profound inhibition of NGF-induced activation of FYN, YES, RAS, and ERK and inhibited neurite outgrowth, NGF-stimulated integrin-directed migration and blocked the NGF-induced conversion of GDP-RAC to its GTP-bound active state. CSK overexpression markedly augmented the activation state of AKT following NGF stimulation. In contrast, kinase-dead CSK augmented the activation of FYN, RAS, and ERK and increased neurite outgrowth. These data suggest a distinct requirement for CSK in the regulation of NGF/TrkA activation of RAS, RAC, ERK, and AKT via the differential control of SFKs in the orchestration of neuronal differentiation.
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PMID:CSK negatively regulates nerve growth factor induced neural differentiation and augments AKT kinase activity. 1589 Mar 37

We demonstrated previously the involvement of a nicotinic acetylcholine receptor containing an alpha7 subunit in the human sperm acrosome reaction (a modified exocytotic event essential to fertilization). Here we report the presence in human sperm of alpha7, alpha9, alpha3, alpha5, and beta4 nicotinic acetylcholine receptor subunits and the following proteins known to be associated with the receptor in the somatic cell: rapsyn and the tyrosine kinases c-SRC and FYN. The alpha7 subunit appears to exist as a homomer in the posterior post-acrosomal and neck regions of sperm and is probably linked to the cytoskeleton via rapsyn. The alpha3, alpha5, and beta4 subunits are present in the sperm flagellar mid-piece of sperm and possibly exist as alpha3alpha5beta4 and/or alpha3beta4 channels. The alpha9 subunit is present in the sperm mid-piece. We detected the FYN and c-SRC tyrosine kinases in the flagellar mid-piece region. Both co-precipitated only with the nicotinic acetylcholine receptor beta4 subunit. Immunolocalization with a C-terminal SRC kinase antibody, which recognizes several members of SRC kinase family, detected a SRC kinase co-localized with the alpha7 subunit in the neck region of sperm. Immunoprecipitation studies with that antibody demonstrated that the alpha7 subunit is associated with a SRC kinase. Antagonists of tyrosine phosphorylation inhibited the acetylcholine-initiated acrosome reaction, suggesting the involvement of a SRC kinase in the acrosome reaction.
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PMID:Nicotinic acetylcholine receptor subunits and associated proteins in human sperm. 1589 3

Src family tyrosine kinases are signaling intermediates in a diverse array of cellular events including cell differentiation, motility, proliferation, and survival. In nonairway smooth muscle cells, muscarinic receptors directly interact with Src family tyrosine kinases. As little is known about the expression and signaling of these Src family tyrosine kinases in human airway smooth muscle cells, we determined the expression of Src family members and characterized the muscarinic receptor-mediated activation of Lyn kinase in these cells. RT-PCR revealed mRNA transcripts for FYN, c-SRC, YES, FRK, and LYN. Fyn, c-Src, Yes, and Lyn were identified in cultured airway smooth muscle cells by immunoblot analysis. In both nontransformed human cultured airway smooth muscle cells and cells transduced with wild-type human Lyn kinase, carbachol increased Lyn kinase activity. Pertussis toxin pretreatment failed to block carbachol activation of Lyn kinase but did attenuate the carbachol-induced increase in ERK/MAPK phosphorylation. Moreover, carbachol inhibited adenylyl cyclase but failed to increase total inositol phosphate synthesis in these cells. The present study shows that Lyn kinase is expressed in human cultured airway smooth muscle cells at both the mRNA and protein levels and that carbachol, an M2 muscarinic receptor agonist in these cells, activates Lyn kinase by a pertussis toxin-insensitive signaling pathway.
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PMID:Expression and muscarinic receptor coupling of Lyn kinase in cultured human airway smooth muscle cells. 1622 19

Human amyloid precursor protein (hAPP) transgenic mice with high levels of amyloid-beta (Abeta) develop behavioral deficits that correlate with the depletion of synaptic activity-related proteins in the dentate gyrus. The tyrosine kinase Fyn is altered in Alzheimer's disease brains and modulates premature mortality and synaptotoxicity in hAPP mice. To determine whether Fyn also modulates Abeta-induced behavioral deficits and depletions of synaptic activity-dependent proteins, we overexpressed Fyn in neurons of hAPP mice with moderate levels of Abeta production. Compared with nontransgenic controls and singly transgenic mice expressing hAPP or FYN alone, doubly transgenic FYN/hAPP mice had striking depletions of calbindin, Fos, and phosphorylated ERK (extracellular signal-regulated kinase), impaired neuronal induction of Arc, and impaired spatial memory retention. These deficits were qualitatively and quantitatively similar to those otherwise seen only in hAPP mice with higher Abeta levels. Surprisingly, levels of active Fyn were lower in high expresser hAPP mice than in NTG controls and lower in FYN/hAPP mice than in FYN mice. Suppression of Fyn activity may result from dephosphorylation by striatal-enriched phosphatase, which was upregulated in FYN/hAPP mice and in hAPP mice with high levels of Abeta. Thus, increased Fyn expression is sufficient to trigger prominent neuronal deficits in the context of even relatively moderate Abeta levels, and inhibition of Fyn activity may help counteract Abeta-induced impairments.
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PMID:Fyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer's disease. 1623 74

To identify novel methylation-silenced genes in gastric cancers, we carried out a chemical genomic screening, a genome-wide search for genes upregulated by treatment with a demethylating agent, 5-aza-2'-deoxycytidine (5-aza-dC). After 5-aza-dC treatment of a gastric cancer cell line (AGS) 579 genes were upregulated 16-fold or more, using an oligonucleotide microarray with 39,000 genes. From these genes, we selected 44 known genes on autosomes whose silencing in gastric cancer has not been reported. Thirty-two of these had CpG islands (CGI) in their putative promoter regions, and all of the CGI were methylated in AGS, giving an estimated number of 421+/-75 (95% confidence interval) methylation-silenced genes. Additionally, we analyzed the methylation status of 16 potential tumor-related genes with promoter CGI that were upregulated four-fold or more, and 14 of these were methylated in AGS. Methylation status of the 32 randomly selected and 16 potential tumor-related genes was analyzed in 10 primary gastric cancers, and 42 genes (ABHD9, ADFP, ALDH1A3, ANXA5, AREG, BDNF, BMP7, CAV1, CDH2, CLDN3, CTSL, EEF1A2, F2R, FADS1, FSD1, FST, FYN, GPR54, GREM1, IGFBP3, IGFBP7, IRS2, KISS1, MARK1, MLF1, MSX1, MTSS1, NT5E, PAX6, PLAGL1, PLAU, PPIC, RBP4, RORA, SCRN1, TBX3, TFAP2C, TNFSF9, ULBP2, WIF1, ZNF177 and ZNF559) were methylated in at least one primary gastric cancer. A metastasis suppressor gene, MTSS1, was located in a genomic region with frequent loss of heterozygosity (8q22), and was expressed abundantly in the normal gastric mucosa, suggesting its role in gastric carcinogenesis. (Cancer Sci 2006; 97: 64 -71).
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PMID:Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. 1636 23

Molecular modeling studies led to the identification of LFM-A13 (alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)propenamide) as a potent inhibitor of Polo-like kinase (Plk). LFM-A13 inhibited recombinant purified Plx1, the Xenopus homolog of Plk, in a concentration-dependent fashion, as measured by autophosphorylation and phosphorylation of a substrate Cdc25 peptide. LFM-A13 was a selective Plk inhibitor. While the human PLK3 kinase was also inhibited by LFM-A13 with an IC(50) value of 61 microM, none of the 7 other serine/threonine kinases, including CDK1, CDK2, CDK3, CHK1, IKK, MAPK1 or SAPK2a, none of the 10 tyrosine kinases, including ABL, BRK, BMX, c-KIT, FYN, IGF1R, PDGFR, JAK2, MET, or YES, or the lipid kinase PI3Kgamma were inhibited (IC(50) values >200-500 microM). The mode of Plk3 inhibition by LFM-A13 was competitive with respect to ATP with a K(i) value of 7.2 microM from Dixon plots. LFM-A13 blocked the cell division in a zebrafish (ZF) embryo model at the 16-cell stage of the embryonic development followed by total cell fusion and lysis. LFM-A13 prevented bipolar mitotic spindle assembly in human breast cancer cells and glioblastoma cells and when microinjected into living epithelial cells at the prometaphase stage of cell division, it caused a total mitotic arrest. Notably, LFM-A13-delayed tumor progression in the MMTV/neu transgenic mouse model of HER2 positive breast cancer at least as effectively as paclitaxel and gemcitabine. LFM-A13 showed a favorable toxicity profile in mice and rats. In particular there was no evidence of hematologic toxicity as documented by peripheral blood counts and bone marrow examinations. These results establish LFM-A13 as a small molecule inhibitor of Plk with in vitro and in vivo anti-proliferative activity against human breast cancer.
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PMID:Anti-breast cancer activity of LFM-A13, a potent inhibitor of Polo-like kinase (PLK). 1709 32

Genomic studies have led to new taxonomic classifications of breast carcinomas. Proteomic investigations using tissue microarrays have yielded complementary results and are useful in identifying potential molecular targets for specific therapies. Searching for new drug targets is particularly important for tumors of poor prognosis, such as breast tumors that lack estrogen receptors and HER2 amplification; in these tumors, certain molecules probably play a significant role in tumor spreading through the stromal microvasculature. We investigated 930 breast carcinomas categorized according to patients' survival (range of follow-up = 4-10 years; median follow-up = 6.5 years) using (1) automated immunohistochemical procedures (Ventana, Cedex, France) with tissue microarrays (Alphelys, Plaisir, France) and (2) quantification of immunoprecipitates assessed by automated image analysis densitometry (SAMBA, Meylan, France). Expression of c-Met and CD146 and that of signaling transducers PI3K, FAK, and FYN were compared in living and deceased patients. Expression of some proteins recently reported to be characteristic of basal cell carcinomas was also assessed, namely, CK5-6, caveolin-1, carbonic anhydrase IX, p63, and CD117; these also constitute potential targets for therapies for aggressive tumors. Overexpression of these proteins was observed in deceased or metastatic patients (P < .01 to P < .00001), particularly node-negative patients (except for FYN, p63, and CD146). c-Met and CD146 are involved in tumor spreading, and our results suggest that they probably play an important role in patients' death, along with other proteins involved in hypoxia (carbonic anhydrase IX) and other cell functions or structures (caveolin-1, CD117, CK5-6, and p63) that are expressed in an aggressive subtype of basal cell carcinoma for which no specific therapy is available.
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PMID:Poor prognosis in breast carcinomas correlates with increased expression of targetable CD146 and c-Met and with proteomic basal-like phenotype. 1791 88

The treatment and management of complex genetic diseases such as osteoporosis can greatly benefit from the integration of relevant research across many different disciplines. We created a text mining tool that analyzes the PubMed literature database and integrates the available genomic information to provide a detailed mapping of the genes and their interrelationships within a particular network such as osteoporosis. The results obtained from our text mining program show that existing genomic data within the PubMed database can effectively be used to predict potentially novel target genes for osteoporosis research that have not previously been reported in the literature. To filter the most significant findings, we developed a ranking system to rate our predicted novel genes. Some of our predicted genes ranked higher than those currently studied, suggesting that they may be of particular interest from a therapeutic standpoint. A preliminary analysis of the current biomedical literature in our research area using our tool suggests that S100A12, as well as a group of SMAD genes previously unstudied in relation to osteoporosis, may be highly relevant to the mechanism of action of bisphosphonates, that the function of osteocytes may be influenced by a family of important interleukins and interleukin-related molecules, and that the FYN oncogene may play an important role in regulating the apoptosis of bone cells in the context of degenerative bone diseases. An evaluation of our tool's predictive ability with an analysis of PubMed literature published before the year 2000 in the area of osteoporosis research shows that many of its top-rated novel target genes from that analysis were later studied and shown to be relevant to osteoporosis in the period between 2000 and 2006. We believe that our tool will be beneficial to researchers in the field of orthopaedics seeking to identify novel target genes in their research area, and it will allow them to delve deeper into the complex interplay between genes, biological systems and diseases.
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PMID:An application of bioinformatics and text mining to the discovery of novel genes related to bone biology. 1732 Apr 99


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