Phosphorylation of the Par-1 polarity kinase by protein kinase D regulates 14-3-3 binding and membrane association

The Par-1 protein kinases are conserved from yeast to humans, where they function as key polarity determinants. The mammalian Par-1 family is comprised of 4 members (Par-1a, -b, -c, and -d). Previously, we demonstrated that atypical protein kinase C (aPKC) phosphorylates the Par-1 kinases on a conse...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2008-11, Vol.105 (47), p.18378-18383
Main Authors: Watkins, Janis L, Lewandowski, Katherine T, Meek, Sarah E.M, Storz, Peter, Toker, Alex, Piwnica-Worms, Helen
Format: Article
Language:English
Subjects:
14-3-3 proteins
14-3-3 Proteins - genetics
14-3-3 Proteins - metabolism
Antibodies
Binding sites
Biological Sciences
Cell Line
Cell Membrane - metabolism
Cell membranes
Cell Polarity
Cells
Enzyme Activation
Gene expression regulation
HeLa cells
Humans
Kinases
Mammals
Membranes
Mutagenesis, Site-Directed
Phosphorylation
Physiological regulation
Polycystic kidney diseases
Protein Binding
Protein Kinase C - genetics
Protein Kinase C - metabolism
Protein Serine-Threonine Kinases - metabolism
Reagents
Tetradecanoylphorbol Acetate - pharmacology
Western blotting
Yeast
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Summary:The Par-1 protein kinases are conserved from yeast to humans, where they function as key polarity determinants. The mammalian Par-1 family is comprised of 4 members (Par-1a, -b, -c, and -d). Previously, we demonstrated that atypical protein kinase C (aPKC) phosphorylates the Par-1 kinases on a conserved threonine residue (T595) to regulate localization and kinase activity. Here, we demonstrate that Par-1b is also regulated by another arm of the PKC pathway, one that involves novel PKCs (nPKC) and protein kinase D. Treatment of cells with the PKC activator phorbol-12-myristate-13-acetate (PMA) potently stimulated phosphorylation of Par-1b on serine 400 (S400), a residue that is conserved in all 4 mammalian Par-1 kinases as well as the fly ortholog. We demonstrate that PMA stimulates nPKC to activate PKD, which in turn directly phosphorylates Par-1b on S400 to positively regulate 14-3-3 binding and to negatively regulate membrane association. Thus, 2 arms of the PKC pathway regulate interactions between Par-1b and 14-3-3 proteins: one involving aPKC and the other nPKC/PKD.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0809661105