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

• 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
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2012.09.002

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