Abstract
BackgroundGlycogen Synthase Kinase 3 (GSK3) has been implicated in regulating chromosomal alignment and mitotic progression but the physiological substrates mediating these GSK3-dependent effects have not been identified. Collapsin Response Mediator Protein 4 (CRMP4) is a cytosolic phosphoprotein known to regulate cytoskeletal dynamics and is a known physiological substrate of GSK3. In this study, we investigate the role of CRMP4 during mitosis.Methodology and Principal FindingsHere we demonstrate that during mitosis CRMP4 phosphorylation is regulated in a GSK3-dependent manner. We show that CRMP4 localizes to spindle microtubules during mitosis and loss of CRMP4 disrupts chromosomal alignment and mitotic progression. The effect of CRMP4 on chromosomal alignment is dependent on phosphorylation by GSK3 identifying CRMP4 as a critical GSK3 substrate during mitotic progression. We also provide mechanistic data demonstrating that CRMP4 regulates spindle microtubules consistent with its known role in the regulation of the microtubule cytoskeleton.Conclusion and SignificanceOur findings identify CRMP4 as a key physiological substrate of GSK3 in regulating chromosomal alignment and mitotic progression through its effect on spindle microtubules.
Highlights
Chromosomal alignment and segregation are important wellcontrolled steps in mitosis
We investigate the role of Collapsin Response Mediator Protein 4 (CRMP4), a known physiological substrate of Glycogen Synthase Kinase 3 (GSK3), during mitosis [31,32]
CRMP4 localizes to spindle microtubules during mitosis Previous studies have shown that CRMP1 and CRMP2 localize to the mitotic spindle [24,25,26]
Summary
Chromosomal alignment and segregation are important wellcontrolled steps in mitosis. This process is largely regulated by the mitotic spindle where microtubules and microtubule binding proteins capture condensed chromosomes by their kinetochores and direct them to the metaphase plate. GSK3 has been implicated in a diverse range of cellular functions including the regulation of mitotic spindle dynamics and chromosomal alignment [2,3,4,5]. Glycogen Synthase Kinase 3 (GSK3) has been implicated in regulating chromosomal alignment and mitotic progression but the physiological substrates mediating these GSK3-dependent effects have not been identified. Collapsin Response Mediator Protein 4 (CRMP4) is a cytosolic phosphoprotein known to regulate cytoskeletal dynamics and is a known physiological substrate of GSK3. We investigate the role of CRMP4 during mitosis
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