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 success of targeting kinases in cancer with small molecule inhibitors has been tempered by the emergence of drug-resistant kinase domain mutations. In patients with chronic myeloid leukemia treated with ABL inhibitors, BCR-ABL kinase domain mutations are the principal mechanism of relapse. Certain mutations are occasionally detected before treatment, suggesting increased fitness relative to wild-type p210 BCR-ABL. We evaluated the oncogenicity of eight kinase inhibitor-resistant BCR-ABL mutants and found a spectrum of potencies greater or less than p210. Although most fitness alterations correlate with changes in kinase activity, this is not the case with the T315I BCR-ABL mutation that confers clinical resistance to all currently approved ABL kinase inhibitors. Through global phosphoproteome analysis, we identified a unique phosphosubstrate signature associated with each drug-resistant allele, including a shift in phosphorylation of two tyrosines (Tyr253 and Tyr257) in the ATP binding loop (P-loop) of BCR-ABL when Thr315 is Ile or Ala. Mutational analysis of these tyrosines in the context of Thr315 mutations demonstrates that the identity of the gatekeeper residue impacts oncogenicity by altered P-loop phosphorylation. Therefore, mutations that confer clinical resistance to kinase inhibitors can substantially alter kinase function and confer novel biological properties that may impact disease progression.
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PMID:Phosphorylation of the ATP-binding loop directs oncogenicity of drug-resistant BCR-ABL mutants. 1716 33

A PG1828 gene-encoded triacylated lipoprotein was previously isolated from a Porphyromonas gingivalis lipopolysaccharide preparation as a Toll-like receptor (TLR) 2 agonist and its lipopeptide derivatives were synthesized based on the chemical structure. In the present study, granulocyte-macrophage colony stimulating factor-differentiated bone marrow-derived dendritic cells (BMDDCs) were stimulated separately with the P. gingivalis synthetic lipopeptide N-palmitoyl-S-[2-pentadecanoyloxy, 3-palmitoyloxy-(2R)-propyl]-l-Cys-Asn-Ser-Gln-Ala-Lys (PGTP2-RL) and its glyceryl stereoisomer (PGTP2-SL). Only PGTP2-RL activated BMDDCs from wild-type mice to secrete tumour necrosis factor-alpha, interleukin (IL)-6, IL-10 and IL-12p40, whilst PGTP2-RL-induced cytokine production was eliminated in TLR2 knockout (-/-) BMDDCs. BMDDCs from wild-type mice but not TLR2-/- mice responded to PGTP2-RL as well as Pam(3)CSK(4) by increasing the expression of maturation markers, including CD80 (B7-1), CD86 (B7-2), CD40, CD275 (B7RP-1/inducible T-cell co-stimulatory ligand) and major histocompatibility complex class II. Taken together, these results indicate that the fatty acid residue at the glycerol position in the P. gingivalis lipopeptide plays a pivotal role in TLR2-mediated dendritic cell activation.
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PMID:Toll-like receptor 2-mediated dendritic cell activation by a Porphyromonas gingivalis synthetic lipopeptide. 1737 84

CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1) is a type I transmembrane glycoprotein expressed in epithelial cells with three or four extracellular domains (ECDs) and either long or short cytoplasmic domain isoforms. We have previously shown that the four extracellular domains, short cytoplasmic domain isoform, CEACAM1-4S, plays an essential role in lumen formation in an in vitro model of mammary morphogenesis. In this study, we transfected MCF-7 cells with either the long or short cytoplasmic domain isoforms of CEACAM1, and grew the cells in humanized mammary mouse fat pads in NOD/SCID mice. In this in vivo model, only the long cytoplasmic domain isoform, CEACAM1-4L, formed glands with lumen. On the basis of other studies that revealed phosphorylation of key Thr and Ser residues in the short cytoplasmic domain, we introduced phosphorylation mimic (for example, Thr or Ser to Asp) or null (Thr or Ser to Ala) mutations into the cytoplasmic domain of CEACAM1-4S and tested them in the in vivo model. Mutation of either Thr or Ser to Asp or the double mutant Thr+Ser to Asp, but not the null mutants, induced gland formation with a central lumen-containing apoptotic cells. Moreover, the phosphorylation mimic mutants of CEACAM1-4S induced downregulation of beta1-integrin, overexpression of beta2-integrin, inhibited phosphorylation of focal adhesion kinase (pTyr-397) and resulted in myofibroblast differentiation as characterized by expression of vimentin, alpha-smooth muscle actin and beta2-integrin, as well as the production of abundant extracellular matrix.
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PMID:Role of CEACAM1 isoforms in an in vivo model of mammary morphogenesis: mutational analysis of the cytoplasmic domain of CEACAM1-4S reveals key residues involved in lumen formation. 1754 42

Lassa virus glycoprotein 2 (LASV GP-2) belongs to the class I fusion protein family. Its N terminus contains two stretches of highly conserved hydrophobic amino acids (residues 260-266 and 276-298) that have been proposed as N-terminal or internal fusion peptide segments (N-FPS, I-FPS) by analogy with similar sequences of other viral glycoproteins or based on experimental data obtained with synthetic peptides, respectively. By using a pH-dependent, recombinant LASV glycoprotein mediated cell-cell fusion assay and a retroviral pseudotype infectivity assay, an alanine scan of all hydrophobic amino acids within both proposed FPSs was performed. Fusogenicity and infectivity were correlated, both requiring correct processing of the glycoprotein precursor. Most point mutations in either FPS accounted for reduced or abolished fusion or infection, respectively. Some mutations also had an effect on pre-fusion steps of virus entry, possibly by inducing structural changes in the glycoprotein. The data demonstrate that several amino acids from both hydrophobic regions of the N terminus, some of which (W264, G277, Y278 and L280) are 100 % conserved in all arenaviruses, are involved in fusogenicity and infectivity of LASV GP-2.
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PMID:Amino acids from both N-terminal hydrophobic regions of the Lassa virus envelope glycoprotein GP-2 are critical for pH-dependent membrane fusion and infectivity. 1762 38

LRP1 [LDL (low-density lipoprotein) receptor-related protein 1]-null CHO cells (Chinese-hamster ovary cells) (13-5-1 cells) exhibited accelerated cell growth and severe tumour progression after they were xenografted into nude mice. Reconstitution of LRP1 expression in these cells, either with the full-length protein or with a minireceptor, reduced growth rate as well as suppressed tumour development. We tested the role of the tyrosine residue in the FXNPXY63 motif within the LRP1 cytoplasmic domain in signal transduction and cell growth inhibition by site-specific mutagenesis. The LRP1 minireceptors harbouring Tyr63 to alanine or Tyr63 to phenylalanine substitution had diametrically opposite effects on cell growth, cell morphology and tumour development in mice. The Y63F-expressing cells showed suppressed cell growth and tumour development, which were associated with decreased beta-catenin and cadherin concentrations in the cells. On the other hand, the Y63A-expressing cells lacked inhibition on cell growth and tumour development, which were associated with hyperactivation of ERKs (extracellular-signal-regulated kinases), FAK (focal adhesion kinase) and cyclin D1 in the cells. The mutant Y63A minireceptor also exhibited reduced capacity in binding to the Dab2 (disabled 2) adaptor protein. In addition, the Y63A mutant showed increased caveolar localization, and cells expressing Y63A had altered caveolae architecture. However, tyrosine to alanine substitution at the other NPXY29 motif had no effect on cell growth or tumorigenesis. These results suggest that the FXNPXY63 motif of LRP1 not only governs cellular localization of the receptor but also exerts multiple functional effects on signalling pathways involved in cell growth regulation.
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PMID:Mutational analysis of the FXNPXY motif within LDL receptor-related protein 1 (LRP1) reveals the functional importance of the tyrosine residues in cell growth regulation and signal transduction. 1790 54

During apoptosis, the pro-apoptotic protein Bax relocalizes from the cytosol to the mitochondrial outer membrane. This relocalization is associated to major conformational changes, namely at the N- and C-terminal ends of the protein. Substitution of residues located at critical positions within the protein potentially stimulates or inhibits this process. In the present study, we investigated the hypothesis that phosphorylation of serine residues might trigger these conformational changes, with a focus on Ser(163) and Ser(184), which have been shown to be phosphorylatable by protein kinases GSK3beta and Akt/PKB, respectively, and on Ser(60), which is located in a consensus target sequence for PKA. Substitutions of these serine residues by alanine or aspartate were done in wild type or previously characterized Bax mutants, and the capacity of the resulting proteins to interact with mitochondria and to release cytochrome c was assayed in yeast, which provides a tool to study the function of Bax, independently of the rest of the apoptotic network. We conclude that sequential phosphorylation of these serine residues might participate in the triggering of the different conformational changes associated with Bax activation during apoptosis.
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PMID:Substitutions of potentially phosphorylatable serine residues of Bax reveal how they may regulate its interaction with mitochondria. 1791 Nov 7

Activation of the serine/threonine protein kinase Akt/PKB is a multi-step process involving membrane recruitment, phosphorylation, and membrane detachment. To investigate this process in the cellular context, we employed a live-cell fluorescence imaging approach to examine conformational changes of Akt and its membrane association. A fluorescence resonance energy transfer-based reporter of Akt action (ReAktion) reveals a conformational change that is critically dependent on the existence of a phosphorylatable threonine 308 in the activation loop, because mutations to either aspartate or alanine abolished the change. Furthermore, a mutant carrying a phosphorylation mimic at this position showed diminished membrane association, suggesting that this phosphorylation plays an important role of promoting the dissociation of activated Akt from the membrane. In addition, the membrane-associating pleckstrin homology domain was found to associate with the catalytic domain when Thr308 is phosphorylated, suggesting such an interdomain interaction as a mechanism by which phosphorylation within the catalytic domain can affect membrane association. These studies uncover new regulatory roles of this critical phosphorylation event of Akt for ensuring its proper activation and function.
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PMID:Live-cell molecular analysis of Akt activation reveals roles for activation loop phosphorylation. 1792 91

In ovo feeding, injecting nutrients into the amnion of the avian embryo, may enhance jejunal nutrient uptake, activity of the intestinal enzymes, and posthatch growth. This hypothesis was tested in the following in ovo feeding (IOF) experiments. In experiment 1, 400 eggs were evenly distributed among 4 nutritional treatments at 23 d of embryonic development (23E) and administered 1 of 4 treatments as a 2 x 2 factorial arrangement of arginine (ARG 0, 0.7%) and beta-hydroxy-beta-methyl-butyrate (HMB 0, 0.1%). Tissues were assayed for maltase, sucrase, and leucine aminopeptidase (LAP) at 25E, hatch, and 3, 7, and 14 d. In experiment 2, all IOF procedures were repeated and treatments were administered at 21E: injected or noninjected control, 21% egg white protein (EWP), 21% EWP + 0.1% HMB. In experiment 3, two hundred eggs were evenly distributed among the following treatments at 23E: noninjected control or 0.7% ARG + 0.1% HMB + 21% EWP. Jejunal samples were assayed for glucose or alanine uptake at 23E, 25E, and hatch (experiment 2), and hatch and 7 d (experiment 3), respectively. All poults were fed a turkey starter diet ad libitum immediately upon hatching. There was a highly significant HMB x ARG interaction on jejunal sucrase, maltase, and LAP activities at 25E and 14 d. Poults in ovo (IO) fed HMB + ARG had approximately a 2- to 3-fold increase in jejunal sucrase, maltase, and LAP activities at 25E, and a 3-fold increase at 14 d, over other treatments. Poults IO fed EWP + HMB (experiment 2) had enhanced glucose uptake at 25E, whereas poults IO fed ARG + HMB + EWP (experiment 3) had enhanced alanine uptake at hatch and 7 d. These studies demonstrate that IOF ARG, HMB, and EWP may enhance jejunal nutrient uptake and digestion in turkeys.
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PMID:The effects of in ovo feeding arginine, beta-hydroxy-beta-methyl-butyrate, and protein on jejunal digestive and absorptive activity in embryonic and neonatal turkey poults. 1795 84

c-Src tyrosine kinase controls proliferation, cell adhesion, and cell migration and is highly regulated. A novel regulatory mechanism to control c-Src function that has recently been identified involves the C-terminal amino acid sequence Gly-Glu-Asn-Leu (GENL) of c-Src as ligand for PDZ domains. Herein, we determined the biological relevance of this c-Src regulation in human breast epithelial cells. The intact GENL sequence maintained c-Src in an inactive state in starved cells and restricted c-Src functions that might lead to metastatic transformation under normal growth conditions. c-Src with a C-terminal Leu/Ala mutation in GENL (Src-A) promoted the activation and translocation of cortactin and focal adhesion kinase and increased the motility and persistence of cell migration on the basement membrane. Src-A promoted increased extracellular proteolytic activity, and in acinar cultures, it led to the escape of cells through the basement membrane into the surrounding matrix. We ascribe the regulatory function of C-terminal Leu to the role of GENL in modulating c-Src activity downstream of cell matrix adhesion. We propose that the C terminus of c-Src via its GENL sequence presents a mechanism that restricts c-Src in epithelia and prevents progression toward an invasive phenotype.
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PMID:c-Src-mediated epithelial cell migration and invasion regulated by PDZ binding site. 1803 57

Oligodendrocyte precursor cells (OPCs) differentiate into oligodendrocytes (OLs) in order to form myelin, which is required for the rapid propagation of action potentials in the vertebrate nervous system. In spite of the considerable clinical importance of myelination, little is known about the basic molecular mechanisms underlying OL differentiation and myelination. Here, we show that cyclin-dependent kinase (Cdk) 5 is activated following the induction of differentiation, and that the Cdk5 inhibitor roscovitine inhibits OL differentiation. The complexity of the OL processes is also diminished after knocking down endogenous Cdk5 using RNAi. We also show that the focal adhesion protein paxillin is directly phosphorylated at Ser244 by Cdk5. Transfection of a paxillin construct harboring a Ser244 to Ala mutation dramatically inhibits its morphological effects. Importantly, phosphorylation of paxillin at Ser244 reduces its interaction with focal adhesion kinase (FAK). Taken together, these results suggest that phosphorylation of paxillin by Cdk5 is a key mechanism in OL differentiation and may ultimately regulate myelination.
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PMID:Cdk5 regulates differentiation of oligodendrocyte precursor cells through the direct phosphorylation of paxillin. 1804 22


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