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)

Akt/PKB is a serine/threonine protein kinase that regulates cell cycle progression, apoptosis and growth factor mediated cell survival in association with tyrosine kinase receptors. The protein is a downstream effector of erbB-2 with implications in breast cancer progression and drug resistance in vitro. We aimed to examine the role of Akt-1 in breast cancer patients, by determining whether the expression (Akt-1) and/or activation (pAkt) were related to prognostic markers and survival. The expression of erbB-2, heregulin beta 1 and Bcl-2 was also assessed by flow cytometry or immunohistochemistry. This study comprised 93 patients, aged <50 who were treated with tamoxifen and/or goserelin. We found that pAkt was associated with lower S-phase fraction (P=0.001) and the presence of heregulin beta 1-expressing stromal cells (P=0.017). Neither Akt-1 nor pAkt was related with other factors. Tumour cells-derived heregulin beta 1 was found mainly in oestrogen receptor negative (P=0.026) and node negative (P=0.005) cases. Survival analysis revealed that pAkt positive patients were more prone to relapse with distant metastasis, independently of S-phase fraction and nodal status (multivariate analysis; P=0.004). The results suggest that activation of Akt may have prognostic relevance in breast cancer.
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PMID:Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients. 1187 May 34

T-cell biological responses appear to involve the complex interaction of T-cell surface receptors, intracellular signaling molecules and the cytoskeleton. Both the serine/threonine protein kinase families protein kinase C (PKC) and protein kinase B or RAC-PK (AKT/PKB) have been implicated in signal transmission leading to activation, differentiation as well as cellular survival of T-lymphocytes. The PKC gene family consists of nine diverse isotypes (PKC alpha, beta, gamma, delta, epsilon, xi, eta, theta; and iota), the AKT/PKB gene family includes three kinases (AKT1/PKB alpha, AKT2/PKB beta, AKT3/PKB gamma). Here, we attempt to summarize the regulation as well as downstream signaling pathways of PKC and AKT/PKB isotypes, that may act additive in TCR/CD28 induced proliferation and survival of peripheral CD4+ T-lymphocytes.
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PMID:Protein kinase C and AKT/protein kinase B in CD4+ T-lymphocytes: new partners in TCR/CD28 signal integration. 1204 76

Integrin-linked kinase (ILK) is an intracellular protein, which interacts with the cytoplasmic domains of integrin beta and beta3 subunits. ILK is a 59 kDa protein containing a phosphoinositide phospholipid-binding domain flanked by an N-terminal ankyrin repeat domain and a C-terminal serine/threonine protein kinase domain. Genetic and biochemical evidence have established an essential role of ILK in connecting integrins to the actin cytoskeleton. Apart from integrins, ILK interacts with several adaptor and signaling proteins resulting in its activation and localization to focal adhesion plaques. The kinase activity of ILK is stimulated upon integrin engagement, as well as by growth factors and chemokines in a PI-3Kinase-dependent manner. ILK can mediate the phosphorylation of a variety of intracellular substrates, most notable of which are: protein kinase B (PKB/Akt), glycogen synthase kinase-3 (GSK-3) and myosin light chain. Gain and loss of function strategies have shown that overexpression, and/or constitutive activation of ILK results in oncogenic transformation and progression to invasive and metastatic phenotypes. In addition ILK expression and activity are upregulated in several types of cancers. In this review, we summarize the adaptor and signaling properties ofILK, and also progress in the identification of therapeutic strategies for inhibition of ILK activity.
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PMID:The role of integrin-linked kinase (ILK) in cancer progression. 1288 12

Self-incompatibility (SI) response in Brassica is initiated by haplotype-specific interactions between the pollen-borne ligand S locus protein 11/SCR and its stigmatic S receptor kinase, SRK. This binding induces autophosphorylation of SRK, which is then thought to trigger a signaling cascade that leads to self-pollen rejection. A recessive mutation of the modifier (m) gene eliminates the SI response in stigma. Positional cloning of M has revealed that it encodes a membrane-anchored cytoplasmic serine/threonine protein kinase, designated M locus protein kinase (MLPK). Transient expression of MLPK restores the ability of mm papilla cells to reject self-pollen, suggesting that MLPK is a positive mediator of Brassica SI signaling.
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PMID:A membrane-anchored protein kinase involved in Brassica self-incompatibility signaling. 1500 63

We found that the expression of mitochondrial apoptosis related genes (Bcl-2 associated protein X, BAX; apoptotic protease activating factor 1, Apaf-1; Caspase 9 and serine/threonine protein kinase, PKB) is elevated in Trichinella spiralis-infected muscles during encapsulation. Micro-dissection of the capsule and subsequent reverse transcription polymerase chain reaction (RT-PCR) confirmed that the expressions of these genes are restricted to the nurse cell. Immunocytochemistry revealed that pro-apoptosis factor (BAX, Apaf-1 and Caspase 9) are predominantly expressed in the basophilic cytoplasm (infected muscle cell origin) and anti-apoptosis factor (PKB) in the eosinophilic cytoplasm (satellite cell origin) of the nurse cell. Electron microscopy revealed that the pre-existing mitochondria in the muscle cells became swollen and disappeared immediately after newborn larva invasion, but new mitochondria of smaller size appeared in the cytoplasm. Nuclear fragmentation and condensation were observed in basophilic cytoplasm which is known to die. Together, the results suggest that the infected muscle cells transform but die through the process of apoptosis which is triggered by factors from the newly formed mitochondria. The anti-apoptosis factor may help the eosinophilic cytoplasm with its survival to ensure nurse cell function.
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PMID:Expression of apoptosis-related factors in muscles infected with Trichinella spiralis. 1507 81

The serum- and glucocorticoid-inducible kinase (SGK) is a serine/threonine protein kinase (PK) transcriptionally regulated by corticoids, serum, and cell volume. SGK regulates cell volume of various cells by effects on Na(+) and K(+) transport through membrane channels. We hypothesized a role for SGK in the activation of volume-sensitive osmolyte and anion channels (VSOACs) in cultured canine pulmonary artery smooth muscle cells (PASMCs). Intracellular dialysis through the patch electrode of recombinant active SGK, but not kinase-dead Delta60-SGK-K127M, heat-inactivated SGK, or active Akt1, partially activated VSOACs under isotonic conditions. Dialysis of active SGK before cell exposure to hypotonic medium significantly accelerated the activation kinetics and increased the maximal density of VSOAC current. Exposure of PASMCs to hypotonic medium (230 mosM) activated phosphatidylinositol 3-kinases (PI3Ks) and their downstream targets Akt/PKB and SGK but not PKC-epsilon. Inhibition of PI3Ks with wortmannin reduced the activation rate and maximal amplitude of VSOACs. Immunoprecipitated ClC-3 channels were phosphorylated by PKC-epsilon but not by SGK in vitro, suggesting that SGK may activate VSOACs indirectly. These data indicate that the PI3K-SGK cascade is activated on hypotonic swelling of PASMCs and, in turn, affects downstream signaling molecules linked to activation of VSOACs.
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PMID:Hypotonic activation of volume-sensitive outwardly rectifying chloride channels in cultured PASMCs is modulated by SGK. 1527 97

HAND2/dHAND is a basic helix-loop-helix transcription factor expressed in the heart and neural crest derivatives during embryogenesis. Although dHAND is essential for branchial arch, cardiovascular and limb development, its target genes have not been identified. The regulatory mechanisms of dHAND function also remain relatively unknown. Here we report that Akt/PKB, a serine/threonine protein kinase involved in cell survival, growth and differentiation, phosphorylates dHAND and inhibits dHAND-mediated transcription. AU5-dHAND expressed in 293T cells became phosphorylated, possibly at its Akt phosphorylation motif, in the absence of kinase inhibitors, whereas the phosphatidylinositol 3-kinase inhibitor wortmannin and the Akt inhibitor NL-71-101, but not the p70 S6 kinase inhibitor rapamycin, significantly reduced dHAND phosphorylation. Coexpression of HA-Akt augmented dHAND phosphorylation at multiple serine and threonine residues mainly located in the bHLH domain and, as a result, decreased the transcriptional activity of dHAND. Consistently, alanine mutation mimicking the nonphosphorylation state abolished the inhibitory effect of Akt on dHAND, whereas aspartate mutation mimicking the phosphorylation state resulted in a loss of dHAND transcriptional activity. These changes in dHAND transcriptional activity were in parallel with changes in the DNA binding activity rather than in dimerization activity. These results suggest that Akt-mediated signaling may regulate dHAND transcriptional activity through the modulation of its DNA binding activity during embryogenesis.
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PMID:Akt-dependent phosphorylation negatively regulates the transcriptional activity of dHAND by inhibiting the DNA binding activity. 1529 10

Akt/PKB is a serine/threonine protein kinase that functions as a critical regulator of cell survival and proliferation. Akt/PKB family comprises three highly homologous members known as PKBalpha/Akt1, PKBbeta/Akt2 and PKBgamma/Akt3 in mammalian cells. Similar to many other protein kinases, Akt/PKB contains a conserved domain structure including a specific PH domain, a central kinase domain and a carboxyl-terminal regulatory domain that mediates the interaction between signaling molecules. Akt/PKB plays important roles in the signaling pathways in response to growth factors and other extracellular stimuli to regulate several cellular functions including nutrient metabolism, cell growth, apoptosis and survival. This review surveys recent developments in understanding the molecular mechanisms of Akt/PKB activation and its roles in cell survival in normal and cancer cells.
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PMID:The activation of Akt/PKB signaling pathway and cell survival. 1578 65

Gastrointestinal peptides including mammalian bombesin-like peptides, cholecystokinin (CCK), gastrin, and neurotensin stimulate DNA synthesis and cell proliferation in cultured cells and are implicated as growth factors in a number of fundamental processes including development, inflammation, tissue regeneration, and neoplastic transformation. These agonists bind to G protein-coupled receptors (GPCRs) that promote Galpha q-mediated activation of beta isoforms of phospholipase C to produce two second messengers: Inositol (1,4,5) trisphosphate {Ins (1, 4, 5) P3} that mobilises Ca2+ from internal stores, and diacylglycerol that activates the classic and new isoforms of the protein kinase C (PKC) family. PKCs play a critical part in transducing bombesin/gastrin releasing peptide (GRP) receptor signals into activation of protein kinase cascades. Protein kinase D (PKD), a serine/threonine protein kinase with distinct structural and enzymological properties, is activated by phosphorylation in living cells through a new PKC-dependent signal transduction pathway. GPCR agonists including bombesin/GRP induce a rapid and striking activation of PKD by PKC. These results indicate that PKD functions downstream from PKCs and identify a new phosphorylation cascade that is activated by gastrointestinal peptide agonists. The bombesin/GRP GPCR also promotes rapid Rho-dependent assembly of focal adhesions, formation of actin stress fibres and tyrosine phosphorylation of multiple cellular proteins. We identified p125 focal adhesion kinase (FAK), p130 Crk-associated substrate (CAS) and paxillin as prominent targets of gastrointestinal peptide-stimulated tyrosine phosphorylation and developed a model that envisages a G12/Rho-dependent pathway connecting GPCR activation to the tyrosine phosphorylation of these focal adhesion proteins. Separate pathways mediate gastrointestinal peptide stimulation of additional tyrosine kinase pathways including transactivation of Src and epidermal growth factor receptor (EGFR). Tyrosine phosphorylation has a critical role in gastrointestinal peptide-induced cellular migration and cooperates with Gq-stimulated events to promote mitogenesis. The growth-promoting effects of neuropeptides and the elucidation of the signalling pathways that mediate their effects assume an added importance because these agonists and their receptors are increasingly implicated in sustaining the proliferation of clinically aggressive solid tumours including those from lung, pancreas, and colon.
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PMID:Gastrointestinal peptide signalling in health and disease. 1614 98

Protein crystallography can be used throughout the drug discovery process to obtain diverse information critical for structure based drug design. At a minimum, a single target structure may be available. Optimally, and especially for protein kinases, a broad range of crystal structures should be obtained to characterize target flexibility, structure modulation via co-factor binding or posttranslational modification, ligand induced conformational changes, and off-target complex structures for selectivity optimization. The flexibility of the protein kinases is in contrast to the need for "crystallizable" constructs, that is, proteins that crystallize under varying conditions and in varying crystal packing arrangements. Strategies to produce crystallizable protein kinase constructs include truncation to the catalytic domain, co-crystallization with rigidifying ligands, crystallization of known rigid forms, and point mutation to improve homogeneity or mimic less crystallizable proteins. PKA, the prototypical serine/threonine protein kinase, and SRC, a tyrosine kinase and the first identified oncoprotein, provide multiple examples of these various approaches to protein kinase crystallography for drug design.
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PMID:Crystallography for protein kinase drug design: PKA and SRC case studies. 1626 79


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