Gravin Is a Transitory Effector of Polo-like Kinase 1 during Cell Division

The mitogenic and second-messenger signals that promote cell proliferation often proceed through multienzyme complexes. The kinase-anchoring protein Gravin integrates cAMP and calcium/phospholipid signals at the plasma membrane by sequestering protein kinases A and C with G protein-coupled receptors...

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Bibliographic Details
Published in:Molecular cell 2012-11, Vol.48 (4), p.547-559
Main Authors: Canton, David A., Keene, C. Dirk, Swinney, Katie, Langeberg, Lorene K., Nguyen, Vivian, Pelletier, Laurence, Pawson, Tony, Wordeman, Linda, Stella, Nephi, Scott, John D.
Format: Article
Language:English
Subjects:
A Kinase Anchor Proteins - genetics
A Kinase Anchor Proteins - metabolism
Animals
biopsy
calcium
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cell Division
Cell Proliferation
cells
chromosomes
cyclic AMP
fluorescence
G-protein coupled receptors
Humans
image analysis
kinases
mass spectrometry
Mice
Mitosis
multienzyme complexes
mutants
neoplasms
phospholipids
Phosphorylation
plasma membrane
Polo-Like Kinase 1
Protein Binding
protein kinases
Protein Serine-Threonine Kinases - metabolism
protein-protein interactions
Proto-Oncogene Proteins - metabolism
threonine
Tumor Cells, Cultured
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Summary:The mitogenic and second-messenger signals that promote cell proliferation often proceed through multienzyme complexes. The kinase-anchoring protein Gravin integrates cAMP and calcium/phospholipid signals at the plasma membrane by sequestering protein kinases A and C with G protein-coupled receptors. In this report we define a role for Gravin as a temporal organizer of phosphorylation-dependent protein-protein interactions during mitosis. Mass spectrometry, molecular, and cellular approaches show that CDK1/Cyclin B1 phosphorylates Gravin on threonine 766 to prime the recruitment of the polo-like kinase Plk1 at defined phases of mitosis. Fluorescent live-cell imaging reveals that cells depleted of Gravin exhibit mitotic defects that include protracted prometaphase and misalignment of chromosomes. Moreover, a Gravin T766A phosphosite mutant that is unable to interact with Plk1 negatively impacts cell proliferation. In situ detection of phospho-T766 Gravin in biopsy sections of human glioblastomas suggests that this phosphorylation event might identify malignant neoplasms. ► Dynamic anchoring of kinases to Gravin ensures the fidelity of mammalian cell division ► CDK1 phosphorylation of Thr766 on Gravin at defined stages of mitosis recruits Plk1 ► Histological detection of phospho-T766 Gravin may be a biomarker for glioblastoma ► Disruption of Plk1-anchoring perturbs cell-cycle progression and cell proliferation
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2012.09.002