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The tumor suppressor APC is an attenuator of spindle-pulling forces during C. elegans asymmetric cell division

View ORCID ProfileKenji Sugioka, Lars-Eric Fielmich, Kota Mizumoto, View ORCID ProfileBruce Bowerman, Sander van den Heuvel, View ORCID ProfileAkatsuki Kimura, View ORCID ProfileHitoshi Sawa
doi: https://doi.org/10.1101/157404
Kenji Sugioka
1Multicellular Organization Laboratory, National Institute of Genetics, 1111 Yata, Mishima, 411-8540 Japan
2RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuoku, Kobe 650-0047 Japan
3Institute of Molecular Biology, University of Oregon, Eugene, OR 97403 USA
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Lars-Eric Fielmich
4Developmental Biology, Biology Department, Science 4 Life, Utrecht University, Padualaan 8, 3584 CH, Utrecht, Netherlands
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Kota Mizumoto
2RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuoku, Kobe 650-0047 Japan
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Bruce Bowerman
3Institute of Molecular Biology, University of Oregon, Eugene, OR 97403 USA
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Sander van den Heuvel
4Developmental Biology, Biology Department, Science 4 Life, Utrecht University, Padualaan 8, 3584 CH, Utrecht, Netherlands
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Akatsuki Kimura
5Cell Architecture Laboratory, National Institute of Genetics, 1111 Yata, Mishima, 411-8540 Japan
6Department of Genetics, School of Life Science, Sokendai, 1111 Yata, Mishima, 411-8540 Japan
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Hitoshi Sawa
1Multicellular Organization Laboratory, National Institute of Genetics, 1111 Yata, Mishima, 411-8540 Japan
2RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuoku, Kobe 650-0047 Japan
6Department of Genetics, School of Life Science, Sokendai, 1111 Yata, Mishima, 411-8540 Japan
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  • ORCID record for Hitoshi Sawa
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Abstract

The adenomatous polyposis coli (APC) tumor suppressor has dual functions in Wnt/ß-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 C. 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 spindle-pulling force attenuation, which may be generally used in asymmetric cell division, and when disrupted potentially contributes to division defects in cancer.

Significance Statement APC (adenomatous polyposis coli) 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 (MTs), 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 C. 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 is the first to document a mechanical role for the APC protein, and provides a physical basis for spindle-pulling force attenuation.

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Posted December 18, 2017.
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The tumor suppressor APC is an attenuator of spindle-pulling forces during C. elegans asymmetric cell division
Kenji Sugioka, Lars-Eric Fielmich, Kota Mizumoto, Bruce Bowerman, Sander van den Heuvel, Akatsuki Kimura, Hitoshi Sawa
bioRxiv 157404; doi: https://doi.org/10.1101/157404
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The tumor suppressor APC is an attenuator of spindle-pulling forces during C. elegans asymmetric cell division
Kenji Sugioka, Lars-Eric Fielmich, Kota Mizumoto, Bruce Bowerman, Sander van den Heuvel, Akatsuki Kimura, Hitoshi Sawa
bioRxiv 157404; doi: https://doi.org/10.1101/157404

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