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Plk4 Regulates Cell Motility through...

Brashavitskaya, Volha.

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Plk4 Regulates Cell Motility through Arhgef1 and Rho GTPase Activation.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Plk4 Regulates Cell Motility through Arhgef1 and Rho GTPase Activation./
Author:	Brashavitskaya, Volha.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
Description:	294 p.
Notes:	Source: Dissertations Abstracts International, Volume: 81-02, Section: B.
Contained By:	Dissertations Abstracts International81-02B.
Subject:	Cellular biology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10976423
ISBN:	9781085579773

Plk4 Regulates Cell Motility through Arhgef1 and Rho GTPase Activation.
Brashavitskaya, Volha.

Plk4 Regulates Cell Motility through Arhgef1 and Rho GTPase Activation. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 294 p.

Source: Dissertations Abstracts International, Volume: 81-02, Section: B.

Thesis (Ph.D.)--University of Toronto (Canada), 2019.

This item is not available from ProQuest Dissertations & Theses.

Cell migration is a fundamental process essential for embryogenesis, immune cell function and maintenance of homeostasis. It is driven primarily by polymerization of the actin cytoskeleton, which is regulated by a family of small Rho GTPases. Rho GTPases Rac1 and Cdc42 are known as the major regulators of actin polymerization and RhoA is mostly thought of as the regulator of actin stress fiber formation and actomyosin contraction. Rho GTPases are activated by GEFs and deactivated by GAPs. Polo-like kinase 4 (Plk4) is well-acknowledged as the master regulator of centriole duplication. Nevertheless, our laboratory has shown that Plk4 activates RhoA during cytokinesis to ensure proper cleavage furrow positioning. We also identified a novel role for Plk4 in regulation of spreading, migration and invasion of normal and cancer cells. However, the mechanisms through which Plk4 regulates these processes are not completely understood. I hypothesized that Plk4 regulates the activation of RhoA and possibly other Rho GTPases to indice cell migration and spreading. In support of this hypothesis, I show here that Plk4 acts as an activator of Rho GTPases RhoA and Rac1 in cycling cells. I also identify 12 GEFs that possess Plk4 consensus phosphorylation motif and show that Plk4 physically interacts with the GEFs Arhgef1 and P-Rex2. Plk4 functionally interacted with Arhgef1 to affect cell migration, showing at least partial dependence of Plk4 migration phenotype on Arhgef1. Further delineation of their interaction showed that Plk4 binds the DH/PH domains and phosphorylates the L-DH/PH fragment of Arhgef1, and that Plk4 enhances Arhgef1 GEF activity. Finally, I show that Plk4 is not likely to activate Arhgef1-RhoA pathway to enhance cell spreading but may act through P-Rex2-Rac1. These results identify a novel mechanism through which Plk4 regulates cell migration. Plk4 has emerged as a potential oncogene, promoter of tumour progression and metastasis formation, prompting the creation of Plk4 inhibitors for therapeutic purposes. The data presented here deepen our understanding of the pathways that may be affected by the Plk4-targeted therapy.

ISBN: 9781085579773Subjects--Topical Terms:

3172791
Cellular biology.
Subjects--Index Terms:

Arhgef1

Plk4 Regulates Cell Motility through Arhgef1 and Rho GTPase Activation.
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245 1 0 $a Plk4 Regulates Cell Motility through Arhgef1 and Rho GTPase Activation.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2019
300 $a 294 p.
500 $a Source: Dissertations Abstracts International, Volume: 81-02, Section: B.
500 $a Advisor: Swallow, Carol J.
502 $a Thesis (Ph.D.)--University of Toronto (Canada), 2019.
506 $a This item is not available from ProQuest Dissertations & Theses.
506 $a This item must not be sold to any third party vendors.
520 $a Cell migration is a fundamental process essential for embryogenesis, immune cell function and maintenance of homeostasis. It is driven primarily by polymerization of the actin cytoskeleton, which is regulated by a family of small Rho GTPases. Rho GTPases Rac1 and Cdc42 are known as the major regulators of actin polymerization and RhoA is mostly thought of as the regulator of actin stress fiber formation and actomyosin contraction. Rho GTPases are activated by GEFs and deactivated by GAPs. Polo-like kinase 4 (Plk4) is well-acknowledged as the master regulator of centriole duplication. Nevertheless, our laboratory has shown that Plk4 activates RhoA during cytokinesis to ensure proper cleavage furrow positioning. We also identified a novel role for Plk4 in regulation of spreading, migration and invasion of normal and cancer cells. However, the mechanisms through which Plk4 regulates these processes are not completely understood. I hypothesized that Plk4 regulates the activation of RhoA and possibly other Rho GTPases to indice cell migration and spreading. In support of this hypothesis, I show here that Plk4 acts as an activator of Rho GTPases RhoA and Rac1 in cycling cells. I also identify 12 GEFs that possess Plk4 consensus phosphorylation motif and show that Plk4 physically interacts with the GEFs Arhgef1 and P-Rex2. Plk4 functionally interacted with Arhgef1 to affect cell migration, showing at least partial dependence of Plk4 migration phenotype on Arhgef1. Further delineation of their interaction showed that Plk4 binds the DH/PH domains and phosphorylates the L-DH/PH fragment of Arhgef1, and that Plk4 enhances Arhgef1 GEF activity. Finally, I show that Plk4 is not likely to activate Arhgef1-RhoA pathway to enhance cell spreading but may act through P-Rex2-Rac1. These results identify a novel mechanism through which Plk4 regulates cell migration. Plk4 has emerged as a potential oncogene, promoter of tumour progression and metastasis formation, prompting the creation of Plk4 inhibitors for therapeutic purposes. The data presented here deepen our understanding of the pathways that may be affected by the Plk4-targeted therapy.
590 $a School code: 0779.
650 4 $a Cellular biology. $3 3172791
653 $a Arhgef1
653 $a GEFs
653 $a migration
653 $a motility
653 $a Plk4
653 $a Rho GTPases
690 $a 0379
710 2 $a University of Toronto (Canada). $b Laboratory Medicine and Pathobiology. $3 3193014
773 0 $t Dissertations Abstracts International $g 81-02B.
790 $a 0779
791 $a Ph.D.
792 $a 2019
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10976423