Edited by Roeland Nusse, Stanford University School of Medicine, Stanford, CA, and approved December 20, 2017 (received for review July 10, 2017)
Adenomatous polyposis coli (APC) is a Wnt signaling component as well as a microtubule-associated protein, and its mutations are frequently associated with colorectal cancers in humans. Although APC stabilizes microtubules, its mechanical role during cell division is largely unknown. Here we show that APC is an attenuator of forces acting on the mitotic spindle during asymmetric cell division of the Caenorhabditis elegans zygote. We performed live imaging, laser microsurgery, and numerical simulation to show how APC suppresses spindle-pulling force generation by stabilizing microtubule plus-ends and reducing microtubule catastrophe frequency at the cell cortex. Our study documents a mechanical role for the APC protein and provides a physical basis for spindle-pulling force attenuation.
The adenomatous polyposis coli (APC) tumor suppressor has dual functions in Wnt/β-catenin signaling and accurate chromosome segregation and is frequently mutated in colorectal cancers. Although APC contributes to proper cell division, the underlying mechanisms remain poorly understood. Here we show that Caenorhabditis elegans APR-1/APC is an attenuator of the pulling forces acting on the mitotic spindle. During asymmetric cell division of the C. elegans zygote, a LIN-5/NuMA protein complex localizes dynein to the cell cortex to generate pulling forces on astral microtubules that position the mitotic spindle. We found that APR-1 localizes to the anterior cell cortex in a Par–aPKC polarity-dependent manner and suppresses anterior centrosome movements. Our combined cell biological and mathematical analyses support the conclusion that cortical APR-1 reduces force generation by stabilizing microtubule plus-ends at the cell cortex. Furthermore, APR-1 functions in coordination with LIN-5 phosphorylation to attenuate spindle-pulling forces. Our results document a physical basis for the attenuation of spindle-pulling force, which may be generally used in asymmetric cell division and, when disrupted, potentially contributes to division defects in cancer.
↵1Present address: Department of Zoology, The University of British Columbia, Vancouver, V6T 1Z3, Canada.
Author contributions: K.S., S.v.d.H., A.K., and H.S. designed research; K.S., L.-E.F., and A.K. performed research; K.M. contributed new reagents/analytic tools; K.S., L.-E.F., B.B., S.v.d.H., A.K., and H.S. analyzed data; and K.S., L.-E.F., B.B., S.v.d.H., A.K., and H.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1712052115/-/DCSupplemental.
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