Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proteins from the PEBP (phosphatidylethanolamine-binding protein) family have been identified in a wide variety of species and are thought to regulate a range of intracellular signalling cascades. The rat homologue (known as RKIP; Raf-1 kinase inhibitor protein) has been shown to negatively regulate the MAP kinase pathway through formation of inhibitory complexes with Raf-1 and MEK. The crystal structure of a new, murine member of the PEBP family, termed mPEBP-2, has been determined. On the basis of amino-acid homology, mPEBP-2 belongs to a distinct subset of the mammalian PEBP proteins. Nonetheless, mPEBP-2 is seen to be very similar in structure to other PEBP proteins from human, bovine and plant sources. Regions of distinctive sequence associated with the PEBP-2 subset are discussed with reference to this structure.
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PMID:The crystal structure of PEBP-2, a homologue of the PEBP/RKIP family. 1203 23

Raf kinase inhibitory protein (RKIP; also known as phosphatidylethanolamine-binding protein or PEBP) is a modulator of the Raf/MAPK signaling cascade and a suppressor of metastatic cancer. Here, we show that RKIP inhibits MAPK by regulating Raf-1 activation; specifically, RKIP acts subsequent to Raf-1 membrane recruitment, prevents association of Raf-1 and p21-activated kinase (PAK), and blocks phosphorylation of the Raf-1 kinase domain by PAK and Src family kinases. Mutation of the PAK and Src phosphorylation sites on Raf-1 to aspartate, a phosphate mimic, prevented RKIP association with or inhibition of Raf-1 signaling. Interestingly, although RKIP can interact with B-Raf, RKIP depletion had no effect on activation of B-Raf. Because c-Raf-1 and B-Raf are both required for maximal MAPK stimulation by epidermal growth factor in neuronal and epithelial cell lines, we determined whether RKIP significantly affects MAPK signaling. In fact, RKIP depletion increased not only the amplitude but also the sensitivity of MAPK and DNA synthesis to epidermal growth factor stimulation by up to an order of magnitude. These results indicate that selective modulation of c-Raf-1 but not B-Raf activation by RKIP can limit the dynamic range of the MAPK signaling response to growth factors and may play a critical role in growth and development.
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PMID:Raf kinase inhibitory protein regulates Raf-1 but not B-Raf kinase activation. 1588 2

Raf kinase inhibitory protein (RKIP or PEBP) is an inhibitor of the Raf/MEK/MAP kinase signaling cascade and a suppressor of cancer metastasis. We now show that RKIP associates with centrosomes and kinetochores and regulates the spindle checkpoint in mammalian cells. RKIP depletion causes decreases in the mitotic index, the number of metaphase cells, and traversal times from nuclear envelope breakdown to anaphase, and an override of mitotic checkpoints induced by spindle poisons. Raf-1 depletion or MEK inhibition reverses the reduction in the mitotic index, whereas hyperactivation of Raf mimics the RKIP-depletion phenotype. Finally, RKIP depletion or Raf hyperactivation reduces kinetochore localization and kinase activity of Aurora B, a regulator of the spindle checkpoint. These results indicate that RKIP regulates Aurora B kinase and the spindle checkpoint via the Raf-1/MEK/ERK cascade and demonstrate that small changes in the MAP kinase (MAPK) pathway can profoundly impact the fidelity of the cell cycle.
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PMID:Raf kinase inhibitory protein regulates aurora B kinase and the spindle checkpoint. 1691 43

In the present report, we investigated the association between the sustained activation of Src family tyrosine kinases (primarily Src kinase) with the biphasic phosphorylation of extracellular signal-regulated kinase (ERK) induced by ischemia in the rat hippocampal CA3/dentate gyrus subfield. Post-ischemia reperfusion resulted in the phosphorylation of ERK in a Ras-dependent manner; down-regulation of NMDA receptors or Src family protein kinases by ketamine or 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo[3,4-d] pyrimidine (PP2) potently antagonized the activation of ERK, indicating that NMDA receptors and Src family tyrosine kinases are essential for the up-regulation of ERK activity following ischemic stimuli. Additionally, an ischemia-induced association between RKIP and Raf-1 resulted in the inhibition of the ERK signaling cascade through an inhibition of Src-mediated Raf-1 phosphorylation at Tyr340/341 residues. This ischemia-induced inhibition of ERK was not associated with other downstream pathways involving Raf-1 phosphorylation at Ser 259 elicited by protein kinase B (Akt). Dissociation of Raf-1 from RKIP by 24 h reperfusion or (4S)-3-[(E)-but-2-enoyl]-4-benzyl-2-oxazolidinone (locostatin) influenced the second phase of ERK activation elicited by the Src-Raf cassette. We propose that, following ischemia, the Src family tyrosine kinases are critical for modulation of the Ras/Raf/MEK/ERK cascade, in which RKIP is involved in biphasic phosphorylation of ERK via a blockade of Src-Raf cascades.
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PMID:Sustained activation of Src-family tyrosine kinases by ischemia: a potential mechanism mediating extracellular signal-regulated kinase cascades in hippocampal dentate gyrus. 1700 55

The phosphatidylethanolamine (PE)-binding protein (PEBP) family is an evolutionary conserved group of proteins found in various species with multiple functions. We identified human PE-binding protein 4 (hPEBP4), a novel member of the PEBP family, as an anti-apoptotic molecule. Here we describe the cloning and functional characterization of the mouse homolog of hPEBP4 (mouse PEBP4, mPEBP4). Full-length cDNA of mPEBP4 contains 1048 bp with an open reading frame (ORF) of 729 bp, which is predicted to encode a 242-aa protein. mPEBP4 contains a PE-binding domain, in this case between amino acids 106 and 213. mPEBP4 localizes primarily to endoplasmic reticulum/Golgi apparatus. Interestingly, RT-PCR and in situ hybridization analyses indicate that mPEBP4 is specifically expressed in mouse eye tissue. We demonstrate that mPEBP4 promotes cellular migration and invasion by inhibiting ERK1/2 and JNK activation and up-regulating the expression of COX-2. In addition, mPEBP4 overexpression inhibits Epirubicin-induced cellular apoptosis. Considering that mPEBP4 is specifically expressed in retinal ganglion cells, whether mPEBP4 is an important molecule involved in visual function needs to be further investigated.
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PMID:Promotion of cellular migration and apoptosis resistance by a mouse eye-specific phosphatidylethanolamine-binding protein. 1714 48

Raf kinase inhibitory protein (RKIP-1) is involved in the regulation of the MAP kinase, NF-kappaB, and GPCR signaling pathways. It is expressed in numerous tissues and cell types and orthologues have been documented throughout the animal and plant kingdoms. RKIP-1 has also been reported as an inhibitor of serine proteases, and a precursor of a neurostimulatory peptide. RKIP-1 has been implicated as a suppressor of metastases in several human cancers. We generated a knockout strain of mice to further assess RKIP-1's function in mammals. RKIP-1 is expressed in many tissues with the highest protein levels detectable in testes and brain. In the brain, expression was ubiquitous in limbic formations, and homozygous mice developed olfaction deficits in the first year of life. We postulate that RKIP-1 may be a modulator of behavioral responses.
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PMID:Raf kinase inhibitory protein knockout mice: expression in the brain and olfaction deficit. 1729 98

Raf kinase inhibitor protein-1 (RKIP-1) belongs to the phosphatidyl ethanolamine-binding family of proteins (PEBP), which are highly conserved throughout evolution and widely expressed in tissues of mammalian organisms. RKIP-1 is a modulator of extracellular signal-regulated kinase (ERK), nuclear factor-kappa B (NF-kappaB), and G protein coupled receptor (GPCR) signaling cascades and is implicated as a factor in numerous physiological processes and disease states including metastasis. Testicular germ cells also express high levels of RKIP mRNA during spermatogenesis, particularly from late pachytene spermatocytes through step 15 elongate spermatids. Therefore, the sensitivity of spermatogenesis to injury was compared in wild-type and RKIP-1(-/-) mice. Unlike what has been described with tumor suppressors such as p53, RKIP-1(-/-) and wild-type mice were equally sensitive to germ cell toxicity by x-irradiation as assessed by terminal deoxynucleotidyl transferase biotin-deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) positivity 9 hours after a 5 Gy exposure and testicular spermatid head counts 15.5 days after 0.5 Gy exposure. Recent findings also indicate that RKIP is a decapacitation factor receptor on sperm. The present study demonstrates that sperm from RKIP-deficient mice are precociously capacitated compared with their wild-type counterparts. Data from mating experiments indicate decreased reproduction rates between crosses of RKIP-1(-/-) male mice and either heterozygous or RKIP-1(-/-) females. Furthermore, RKIP immunolocalization of epididymal sperm supports transfer of the protein from germ cell cytoplasm to the sperm via the cytoplasmic droplet during epididymal transport. Overall, these studies indicate an important role for RKIP in reproduction as a modulator of capacitation but not in the regulation of testicular injury.
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PMID:Mice lacking Raf kinase inhibitor protein-1 (RKIP-1) have altered sperm capacitation and reduced reproduction rates with a normal response to testicular injury. 1755 9

Raf kinase inhibitory protein (RKIP/PEBP1), a member of the phosphatidylethanolamine binding protein family that possesses a conserved ligand-binding pocket, negatively regulates the mammalian mitogen-activated protein kinase (MAPK) signaling cascade. Mutation of a conserved site (P74L) within the pocket leads to a loss or switch in the function of yeast or plant RKIP homologues. However, the mechanism by which the pocket influences RKIP function is unknown. Here we show that the pocket integrates two regulatory signals, phosphorylation and ligand binding, to control RKIP inhibition of Raf-1. RKIP association with Raf-1 is prevented by RKIP phosphorylation at S153. The P74L mutation increases kinase interaction and RKIP phosphorylation, enhancing Raf-1/MAPK signaling. Conversely, ligand binding to the RKIP pocket inhibits kinase interaction and RKIP phosphorylation by a noncompetitive mechanism. Additionally, ligand binding blocks RKIP association with Raf-1. Nuclear magnetic resonance studies reveal that the pocket is highly dynamic, rationalizing its capacity to interact with distinct partners and be involved in allosteric regulation. Our results show that RKIP uses a flexible pocket to integrate ligand binding- and phosphorylation-dependent interactions and to modulate the MAPK signaling pathway. This mechanism is an example of an emerging theme involving the regulation of signaling proteins and their interaction with effectors at the level of protein dynamics.
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PMID:Raf kinase inhibitory protein function is regulated via a flexible pocket and novel phosphorylation-dependent mechanism. 1910 40

The mitogen-activated protein kinase cascade is a conserved signal transduction pathway found in organisms of complexity spanning from yeast to humans. In many mammalian tissue types, this pathway can correctly transduce signals from different extracellular messengers, leading to specific and often mutually exclusive cellular responses. The transduced signal is tuned by a complicated set of positive and negative feedback control mechanisms and fed into a downstream gene expression network. This network, based on the immediate early gene system, has two possible, mutually exclusive outcomes. Using a mathematical model, we study how different stimuli lead to different temporal signal structure. Further, we investigate how each of the feedback controls contributes to the overall specificity of the gene expression output, and hypothesize that the complicated nature of the mammalian mitogen-activated protein kinase pathway results in a system able to robustly identify and transduce the proper signal without investing in two completely separate signal cascades. Finally, we quantify the role of the RKIP protein in shaping the signal, and propose a novel mechanism of its involvement in cancer metastasis.
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PMID:Specificity and robustness of the mammalian MAPK-IEG network. 1941 54

The mechanisms underlying prostate cancer progression are poorly understood. Proteins responsive to androgens may be involved in the development and progression of prostate cancer and the ultimate failure of androgen-ablation therapy. Therapy with somatostatin (sms) analogues could be a possible therapeutic alternative to chemotherapy in hormone refractory prostate cancer patients. We used two prostate cancer cell-lines, LNCaP (androgen-dependent) and DU145 (androgen-independent), to compare the protein expressions. Both cell lines were treated with sms and its derivative smsdx. Smsdx is a glycosylated poly sms with high stability suitable for clinical use. A comparison study of protein expression was analyzed by means of two-dimensional gel electrophoresis (2DE) followed by mass spectrometric analysis. Marked quantitative differences were observed in the protein expression profiles in sms/smsdx treated LNCaP and DU145 cells compared to the control cells. One third of the detected proteins were differentially expressed (PRDXs, hnRNPs, HSPs, RKIP). Concordance in protein expression patterns was observed between smsdx and sms treated cells with strong agreement between the up- and down-regulation of proteins. Fifty-eight (isoforms of 49 proteins) protein spots were identified and found differentially expressed at 2-fold change between LNCaP and DU145 cells. Thirty-one proteins in LNCaP have higher expressions than in DU145. Twenty-seven proteins in DU145 have higher expressions than in LNCaP. Most of the differentially expressed proteins (2-fold) between LNCaP and DU145 cells were affected by sms/smsdx treatment (1.2- to 2.6-fold change). Sms/smsdx affects the mitochondria of prostate cancer cells in a way that eventually triggers mitochondrial-mediated apoptosis. Regulation of certain proteins (e.g., RKIP, VDACs) by sms/smsdx suggests that sms/smsdx exerts its effects on prostate cancer cells via MAPK pathway and by regulating the activities of phosphotyrosine phosphatases.
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PMID:Comparison of protein expression in two prostate cancer cell-lines, LNCaP and DU145, after treatment with somatostatin. 1988 99


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