Protein Kinase D2 Modulates Cell Cycle By Stabilizing Aurora A Kinase at Centrosomes

Molecular Cancer Research : MCR
Adhiraj RoyQiming Jane Wang

Abstract

Aurora A kinase (AURKA) is a master cell-cycle regulator that is often dysregulated in human cancers. Its overexpression has been associated with genome instability and oncogenic transformation. The protein kinase D (PKD) family is an emerging therapeutic target of cancer. Aberrant PKD activation has been implicated in tumor growth and survival, yet the underlying mechanisms remain to be elucidated. This study identified, for the first time, a functional crosstalk between PKD2 and Aurora A kinase in cancer cells. The data demonstrate that PKD2 is catalytically active during the G2-M phases of the cell cycle, and inactivation or depletion of PKD2 causes delay in mitotic entry due to downregulation of Aurora A, an effect that can be rescued by overexpression of Aurora A. Moreover, PKD2 localizes in the centrosome with Aurora A by binding to γ-tubulin. Knockdown of PKD2 caused defects in centrosome separation, elongated G2 phase, mitotic catastrophe, and eventually cell death via apoptosis. Mechanistically, PKD2 interferes with Fbxw7 function to protect Aurora A from ubiquitin- and proteasome-dependent degradation. Taken together, these results identify PKD as a cell-cycle checkpoint kinase that positively modulates G2-M transitio...Continue Reading

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Citations

Feb 9, 2020·International Journal of Molecular Sciences·Amanda C LeightnerEric D Jensen
Feb 20, 2021·Experimental Biology and Medicine·Stephanie Colón-MarreroHarold I Saavedra
May 20, 2021·Cell Reports·Evanthia PangouIzabela Sumara
Dec 22, 2021·Nucleic Acids Research·Jiajia LiuXiaobo Zhou

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