Chromokinesins: localization-dependent functions and regulation during cell division
ABSTRACT The bipolar spindle is a highly dynamic structure that assembles transiently around the chromosomes and provides the mechanical support and the forces required for chromosome segregation. Spindle assembly and chromosome movements rely on the regulation of microtubule dynamics and a fine balance of forces exerted by various molecular motors. Chromosomes are themselves central players in spindle assembly. They generate a RanGTP gradient that triggers microtubule nucleation and stabilization locally and they interact dynamically with the microtubules through motors targeted to the chromatin. We have previously identified and characterized two of these so-called chromokinesins: Xkid (kinesin 10) and Xklp1 (kinesin 4). More recently, we found that Hklp2/kif15 (kinesin 12) is targeted to the chromosomes through an interaction with Ki-67 in human cells and is therefore a novel chromokinesin. Hklp2 also associates with the microtubules specifically during mitosis, in a TPX2 (targeting protein for Xklp2)-dependent manner. We have shown that Hklp2 participates in spindle pole separation and in the maintenance of spindle bipolarity in metaphase. To better understand the function of Hklp2, we have performed a detailed domain analysis. Interestingly, from its positioning on the chromosome arms, Hklp2 seems to restrict spindle pole separation. In the present review, we summarize the current knowledge of the function and regulation of the different kinesins associated with chromosome arms during cell division, including Hklp2 as a novel member of this so-called chromokinesin family.
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ABSTRACT: Microtubule-based motor proteins play key roles during mitosis to assemble the bipolar spindle, define the cell division axis, and align and segregate the chromosomes. The majority of mitotic motors are members of the kinesin superfamily. Despite sharing a conserved catalytic core, each kinesin has distinct functions and localization, and is uniquely regulated in time and space. These distinct behaviors and functional specificity are generated by variations in the enzymatic domain as well as the non-conserved regions outside of the kinesin motor domain and the stalk. These flanking regions can directly modulate the properties of the kinesin motor through dimerization or self-interactions, and can associate with extrinsic factors, such as microtubule or DNA binding proteins, to provide additional functional properties. This review discusses the recently identified molecular mechanisms that explain how the control and functional specification of mitotic kinesins is achieved. © 2013 Wiley Periodicals, Inc.Cytoskeleton 09/2013; 70(9). DOI:10.1002/cm.21135 · 3.01 Impact Factor
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ABSTRACT: Mitotic spindles are self-organizing protein machines that harness teams of multiple force generators to drive chromosome segregation. Kinesins are key members of these force-generating teams. Different kinesins walk directionally along dynamic microtubules, anchor, crosslink, align and sort microtubules into polarized bundles, and influence microtubule dynamics by interacting with microtubule tips. The mechanochemical mechanisms of these kinesins are specialized to enable each type to make a specific contribution to spindle self-organization and chromosome segregation.Nature Reviews Molecular Cell Biology 03/2014; 15(4):257-71. DOI:10.1038/nrm3768 · 36.46 Impact Factor
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ABSTRACT: The centrosome is the main microtubule (MT)-organizing centre of animal cells. It consists of two centrioles and a multi-layered proteinaceous structure that surrounds the centrioles, the so-called pericentriolar material. Centrosomes promote de novo assembly of MTs and thus play important roles in Golgi organization, cell polarity, cell motility and the organization of the mitotic spindle. To execute these functions, centrosomes have to adopt particular cellular positions. Actin and MT networks and the association of the centrosomes to the nuclear envelope define the correct positioning of the centrosomes. Another important feature of centrosomes is the centrosomal linker that connects the two centrosomes. The centrosome linker assembles in late mitosis/G1 simultaneously with centriole disengagement and is dissolved before or at the beginning of mitosis. Linker dissolution is important for mitotic spindle formation, and its cell cycle timing has profound influences on the execution of mitosis and proficiency of chromosome segregation. In this review, we will focus on the mechanisms of centrosome positioning and separation, and describe their functions and mechanisms in the light of recent findings.