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Molecular Pharmacology

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Review ArticleMinireview

Regulation of Protein Kinase D1 Activity

Susan F. Steinberg
Molecular Pharmacology March 2012, 81 (3) 284-291; DOI: https://doi.org/10.1124/mol.111.075986
Susan F. Steinberg
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Abstract

Protein kinase D1 (PKD1) is a stress-activated serine/threonine kinase that plays a vital role in various physiologically important biological processes, including cell growth, apoptosis, adhesion, motility, and angiogenesis. Dysregulated PKD1 expression also contributes to the pathogenesis of certain cancers and cardiovascular disorders. Studies to date have focused primarily on the canonical membrane-delimited pathway for PKD1 activation by G protein-coupled receptors or peptide growth factors. Here, agonist-dependent increases in diacylglycerol accumulation lead to the activation of protein kinase C (PKC) and PKC-dependent phosphorylation of PKD1 at two highly conserved serine residues in the activation loop; this modification increases PKD1 catalytic activity, as assessed by PKD1 autophosphorylation at a consensus phosphorylation motif at the extreme C terminus. However, recent studies expose additional controls and consequences for PKD1 activation loop and C-terminal phosphorylation as well as additional autophosphorylation reactions and trans-phosphorylations (by PKC and other cellular enzymes) that contribute to the spatiotemporal control of PKD1 signaling in cells. This review focuses on the multisite phosphorylations that are known or predicted to influence PKD1 catalytic activity and may also influence docking interactions with cellular scaffolds and trafficking to signaling microdomains in various subcellular compartments. These modifications represent novel targets for the development of PKD1-directed pharmaceuticals for the treatment of cancers and cardiovascular disorders.

Footnotes

  • This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grant HL77860].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.111.075986.

  • ABBREVIATIONS:

    PKD
    protein kinase D
    PH
    pleckstrin homology
    PKC
    protein kinase C
    nPKC
    novel PKC isoform (δ, ε, η, θ)
    AR
    adrenergic receptor
    CREB
    cAMP response element-binding protein
    cTnI
    cardiac troponin I
    NFκB
    nuclear factor κB
    WT
    wild type
    PMA
    phorbol 12-myristate 13-acetate
    SB203580
    4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole
    DYRK
    dual-specificity tyrosine-phosphorylation regulated kinase
    GSK-3
    glycogen synthase kinase-3
    Gö6976
    12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole
    HADC
    histone deacetylase
    BPKDi
    bipyridyl PKD inhibitor
    PSSA
    phosphorylation site-specific antibody
    PDZ
    postsynaptic density 95/discs-large/zona occludens
    JNK
    c-jun-N-terminal kinase.

  • Received September 20, 2011.
  • Accepted December 21, 2011.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 81 (3)
Molecular Pharmacology
Vol. 81, Issue 3
1 Mar 2012
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Review ArticleMinireview

PKD1 Phosphorylation

Susan F. Steinberg
Molecular Pharmacology March 1, 2012, 81 (3) 284-291; DOI: https://doi.org/10.1124/mol.111.075986

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Review ArticleMinireview

PKD1 Phosphorylation

Susan F. Steinberg
Molecular Pharmacology March 1, 2012, 81 (3) 284-291; DOI: https://doi.org/10.1124/mol.111.075986
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