|WINEY, MARK - University Of Colorado|
|STUMPF, JASON - University Of Washington|
|WORDEMAN, LINDA - University Of Washington|
Submitted to: Cell Cycle
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/26/2011
Publication Date: 3/1/2011
Citation: Mattison, C.P., Winey, M., Stumpf, J., Wordeman, L. 2011. Mip1 associates with both the Mps1 kinase and actin and is required for cell cortex stability and anaphase spindle positioning. Cell Cycle. 10(5):783-93.
Interpretive Summary: Cancer cells often have an incorrect number of chromosomes. An incorrect number of chromosomes in cancer cells can arise from improper cell division during growth. Several cell proteins involved in cell structure and information processing (cell signaling) are essential for proper cell division. We have identified a new structural protein whose function is essential for cell division during growth. This new protein (Mip1) interacts with a known cell signaling protein (Mps1), and is essential for the structural integrity of the cell and separation of chromosomes during division. This new protein localizes to several important cell structures during division, and loss of this protein causes severe defects during division, resulting in cells with incorrect numbers of chromosomes. Further study of the Mip1 protein could provide an excellent target for cancer therapeutics.
Technical Abstract: The Mps1 family of protein kinases contributes to cell cycle control by regulating multiple microtubule cytoskeleton activities. We have uncovered a new Mps1 substrate that provides a novel link between Mps1 and the actin cytoskeleton. We have identified a conserved human Mps1 (hMps1) interacting protein we have termed Mps1 interacting protein-1 (Mip1). Mip1 defines an uncharacterized family of conserved proteins that contain coiled-coil and calponin homology domains. We demonstrate that Mip1 is a phosphoprotein that interacts with hMps1 in vitro and in vivo and is an hMps1 substrate. Mip1 exhibits dynamic localization during the cell cycle. Mip1 localizes to the actin cytoskeleton during interphase, the spindle early in mitosis, and the cleavage furrow during cytokinesis. Mip1 function is required to ensure proper spindle positioning at the onset of anaphase after cells begin furrow ingression during anaphase. Cells depleted of Mip1 exhibit aberrant mitotic actin filament organization, excessive membrane blebbing, dramatic spindle rocking, and chromosome distribution. Errors during early cytokinesis produce high numbers of binucleate cells. Our data indicate that Mip1 is a newly recognized component of the actin cytoskeleton that interacts with hMps1, and that is essential to ensure proper segregation of the genome during cell cleavage.