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  • 1
    Keywords: CANCER ; CELLS ; INHIBITOR ; INVASION ; tumor ; CELL ; COMBINATION ; Germany ; INHIBITION ; KINASE ; PATHWAY ; THERAPY ; DISEASE ; DISEASES ; SITE ; PROTEIN ; COMPLEX ; COMPLEXES ; MECHANISM ; DOMAIN ; BINDING ; PHOSPHORYLATION ; protein kinase ; PROTEIN-KINASE ; treatment ; CATALYTIC SUBUNIT ; inactivation ; FIBER ; ADHESION ; ATP ; CELL-ADHESION ; crystal structure ; CRYSTAL-STRUCTURE ; MUSCLE ; PKA ; PROTEIN-KINASES
    Abstract: Protein kinases require strict inactivation to prevent spurious cellular signaling; overactivity can cause cancer or other diseases and necessitates selective inhibition for therapy. Rho-kinase is involved in such processes as tumor invasion, cell adhesion, smooth muscle contraction, and formation of focal adhesion fibers, as revealed using inhibitor Y-27632. Another Rho-kinase inhibitor, HA-1077 or Fasudil, is currently used in the treatment of cerebral vasospasm; the related nanomolar inhibitor H-1152P improves on its selectivity and potency. We have determined the crystal structures of HA-1077, H-1152P, and Y-27632 in complexes with protein kinase A (PKA) as a surrogate kinase to analyze Rho-kinase inhibitor binding properties. Features conserved between PKA and Rho-kinase are involved in the key binding interactions, while a combination of residues at the ATP binding pocket that are unique to Rho-kinase may explain the inhibitors' Rho-kinase selectivity. Further, a second H-1152P binding site potentially points toward PKA regulatory domain interaction modulators
    Type of Publication: Journal article published
    PubMed ID: 14656443
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  • 2
    Keywords: PEPTIDE ; CANCER ; CELLS ; IONIZING-RADIATION ; Germany ; INHIBITION ; KINASE ; PROTEIN ; TIME ; ACTIVATION ; cell cycle ; CELL-CYCLE ; CYCLE ; PROTEIN-KINASE ; SEQUENCE ; ACID ; antibodies ; antibody ; CATALYTIC SUBUNIT ; SUBUNIT ; SIGNAL-TRANSDUCTION ; PROTEIN-KINASES ; OKADAIC ACID ; PHORBOL ESTER ; TYROSINE PHOSPHORYLATION ; MITOSIS ; MOLECULAR-CLONING ; EPIDERMAL-GROWTH-FACTOR ; RE ; RESIDUES ; TRANSITION ; ENZYME-ACTIVITIES ; ENZYME ; PHASE ; CELL-DIVISION ; KINASES ; downregulation ; DEPENDENT PHOSPHORYLATION ; G2 inhibition ; G2/mitosis ; histone H1 ; PP2A ; TPA ; unscheduled reactivation
    Abstract: In the cell cycle the transition from G2 phase to cell division (M) is strictly controlled by protein phosphorylation-dephosphorylation reactions effected by several protein kinases and phosphatases. Although much indirect and direct evidence point to a key role of protein phosphatase 2A (PP2A) at the G2/M transition, the control of the enzyme activity prior to and after the transition are not fully clarified. Using synchronized HeLa cells we determined the PP2A activity (i.e. the increment sensitive to inhibition by 2 nM okadaic acid) in immunoprecipitates obtained with antibodies raised against a conserved peptide sequence (residues 169-182, Ab(169/182)) of the PP2A catalytic subunit (PP2A C). Two different substrates were offered: the phospho-peptide KR(p)TIRR and historic H1 phosphorylated by means of the cyclin-dependent protein kinase p34(cdc2). The results indicate that in HeLa cells the specific activity of PP2A towards both substrates goes through a minimum in late G2 phase and stays low until metaphase. Treatment of G2 cells with TPA (10(-7) M) caused a reactivation of the downregulated PP2A activity within 20 min, i.e. the same time frame within which TPA was shown earlier to block HeLa cells at the transition from G2 to mitosis [Kinzel et al., 1988. Cancer Res. 48, 1759-1762]. Activation of PP2A was also induced by TPA in mitotic cells. The low activity of PP2A in mitotic cells was accompanied by a strong reaction of mitotic PP2A C with anti-P-Tyr antibodies in Western blots, which was reversed by treatment of mitotic cells with TPA. The results suggest that the activity of cellular PP2A requires downregulation for the transition from G2 phase to mitosis. Unscheduled reactivation of PP2A induced by TPA in late G2 phase appears to inhibit the progress into mitosis. (c) 2005 Elsevier GmbH. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16180310
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  • 3
    Keywords: PEPTIDE ; GROWTH-FACTOR ; Germany ; KINASE ; PATHWAY ; PATHWAYS ; SITE ; PROTEIN ; TRANSDUCTION ; LIGAND ; MECHANISM ; FAMILY ; PHOSPHORYLATION ; protein kinase ; PROTEIN-KINASE ; signal transduction ; SIGNAL ; CATALYTIC SUBUNIT ; ARRANGEMENT ; ESCHERICHIA-COLI ; SIGNAL-TRANSDUCTION ; MODULATION ; ATP ; PKA ; PLASMA-MEMBRANE ; Jun ; PROJECT ; FLEXIBILITY ; max ; STATES ; signaling ; STANDARD ; ABSENCE ; VARIANT ; CRYSTAL-STRUCTURES ; DEAMIDATION ; DEPENDENCE ; DEPENDENT PROTEIN-KINASE
    Abstract: Protein kinases comprise the major enzyme family critically involved in signal transduction pathways; posttranslational modifications affect their regulation and determine signaling states. The prototype protein kinase A (PKA) possesses an N-terminal alpha-helix (Helix A) that is atypical for kinases and is thus a major distinguishing feature of PKA. Its physiological function may involve myristoylation at the N-terminus and modulation via phosphorylation at serine 10. Here we describe an unusual structure of an unmyristoylated PKA, unphosphorylated at serine 10, with a completely ordered N-terminus. Using standard conditions (e.g., PKI 5-24, ATP site ligand, MEGA-8), a novel 2-fold phosphorylated PKA variant showed the ordered N-terminus in a new crystal packing arrangement. Thus, the critical factor for structuring the N-terminus is apparently the absence of phosphorylation of Ser10. The flexibility of the N-terminus, its myristoylation, and the conformational dependence on the phosphorylation state are consistent with a functional role for myristoylation
    Type of Publication: Journal article published
    PubMed ID: 15196017
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