Polo-like kinase 1 phosphorylation of p150 ^Glued facilitates nuclear envelope breakdown during prophase

Abstract

Nuclear envelope breakdown (NEBD) is an essential step during the G2/M transition in higher eukaryotic cells. Increasing evidence supports the notion that both microtubules and microtubuleassociated motor proteins are critical regulators of NEBD. Although it has been described that p150 Glued , the major component of the dynein/dynactin complex, localizes in the nuclear envelope during prophase, the exact role of p150 Glued and its regulation during NEBD are largely elusive. Polo-like kinase 1 (Plk1), the best characterized Ser/Thr kinase, is involved in mitotic entry in several systems; however, the targets of Plk1 during NEBD are unknown. Herein, we show that in mammalian cells both Plk1 and p150 Glued regulate NEBD and that Plk1 interacts with and phosphoryates p150 Glued during NEBD at prophase. Using various approaches, we showed that Plk1 phosphorylates p150 Glued at Ser-179 and that the pS179 epitope is generated at the nuclear envelope of prophase cells. Significantly, Plk1-mediated phosphorylation of p150 Glued at Ser-179 positively regulates its accumulation at the nuclear envelope during prophase. Finally, we found that cells expressing the Plk1-unphosphorylatable mutant (p150 Glued -S179A) arrest at G2, as indicated by reduced NEBD, increased levels of cyclin B and phospho-H3, but a decreased level of Cdc2 kinase activity. Taking these data together, we conclude that Plk1 phosphorylation of p150 Glued might be one major pathway of NEBD regulation. mitosis | microtubule dynamics | dynactin

Cooperative Phosphorylation of FADD by Aur-A and Plk1 in Response to Taxol Triggers Both Apoptotic and Necrotic Cell Death

“…Such a cooperative phosphorylation by Aur-A and Plk1 has not previously been reported. Kif2a, Bora, and p150 glued are also phosphorylated by Aur-A and Plk1; however, cooperative phosphorylation has not been shown (41)(42)(43)(44). Therefore, this study presents a novel regulatory mechanism involving the action of Aur-A and Plk1 upon their common substrate, FADD.…”

Cotargeting Polo-Like Kinase 1 and the Wnt/β-Catenin Signaling Pathway in Castration-Resistant Prostate Cancer

“…Glued (38), two microtubule plus-end binding proteins, enhances microtubule dynamics, consequently contributing to taxel resistance (39). Fourth, Plk1 phosphorylation of the PTEN tumor suppressor causes its inactivation and, thus, activation of the phosphatidylinositol 3-kinase (PI3K)-AKT-mTOR pathway, a major driving force for PCa progression (40).…”

Low-dose arsenic-mediated metabolic shift is associated with activation of Polo-like kinase 1 (Plk1)

“…12 For example, we previously showed that Plk1 phosphorylation of Orc2 and Hbo1, 2 members of DNA replication machinery, promotes DNA replication under stressful conditions, 32,33 eventually contributing to acquisition of resistance to drugs that inhibit DNA replication, such as gemcitabine. 34 We also showed that Plk1 phosphorylation of CLIP-170 and p150 Glued , 2 microtubule plus-end binding proteins, enhances tubulin dynamics, 35,36 thus contributing to development of resistance to taxol. 37 In addition, Plk1 elevation causes activation of androgen de novo biosynthesis pathway, eventually resulting in resistance to androgen receptor inhibitors, such as enzalutamide and abiraterone, 2 major drugs used for patients with castration-resistant prostate cancer.…”