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. 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.
Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
David A
DA
Canton
C Dirk
CD
Keene
Katie
K
Swinney
Lorene K
LK
Langeberg
Vivian
V
Nguyen
Laurence
L
Pelletier
Tony
T
Pawson
Linda
L
Wordeman
Nephi
N
Stella
John D
JD
Scott
D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division; D049109:Cell Proliferation; D006801:Humans; D051379:Mice; D008938:Mitosis; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000097869:Polo-Like Kinase 1
D054758:A Kinase Anchor Proteins; D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C491162:AKAP12 protein, human