TY - JOUR
T1 - Cyclin-dependent kinase 1-mediated phosphorylation of SET at serine 7 is essential for its oncogenic activity
AU - Yin, Ling
AU - Zeng, Yongji
AU - Xiao, Yi
AU - Chen, Yuanhong
AU - Shen, Hong
AU - Dong, Jixin
N1 - Funding Information:
All fluorescence images were acquired at the Advanced Microscopy Core at the University of Nebraska Medical Center. The core is supported in part by the grant P30 GM106397 from the National Institutes of Health (NIH). Research in the Dong laboratory is supported by Fred & Pamela Buffett Cancer Center support grant (P30 CA036727), and grants P30 GM106397 and R01 GM109066 from the NIH. L.Y. and Y.Z. are supported by fellowships from Chinese Scholarship Council, China. We also thank Dr Joyce Solheim for critical reading and comments on the manuscript.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/6/1
Y1 - 2019/6/1
N2 - SE translocation (SET), an inhibitor of protein phosphatase 2A (PP2A), plays important roles in mitosis and possesses oncogenic activity in several types of cancer. However, little is known regarding its regulation. Here we reveal a novel phosphorylation site of SET isoform 1, and we have determined its biological significance in tumorigenesis. We found that the mitotic kinase cyclin-dependent kinase 1 (CDK1) phosphorylates SET isoform 1 in vitro and in vivo at serine 7 during antitubulin drug-induced mitotic arrest and normal mitosis. SET deletion resulted in massive multipolar spindles, chromosome misalignment and missegregation, and centrosome amplification during mitosis. Moreover, mitotic phosphorylation of SET isoform 1 is required for cell migration, invasion, and anchorage-independent growth in vitro and tumorigenesis in xenograft animal models. We further documented that SET phosphorylation affects Akt activity. Collectively, our findings suggest that SET isoform 1 promotes oncogenesis in a mitotic phosphorylation-dependent manner.
AB - SE translocation (SET), an inhibitor of protein phosphatase 2A (PP2A), plays important roles in mitosis and possesses oncogenic activity in several types of cancer. However, little is known regarding its regulation. Here we reveal a novel phosphorylation site of SET isoform 1, and we have determined its biological significance in tumorigenesis. We found that the mitotic kinase cyclin-dependent kinase 1 (CDK1) phosphorylates SET isoform 1 in vitro and in vivo at serine 7 during antitubulin drug-induced mitotic arrest and normal mitosis. SET deletion resulted in massive multipolar spindles, chromosome misalignment and missegregation, and centrosome amplification during mitosis. Moreover, mitotic phosphorylation of SET isoform 1 is required for cell migration, invasion, and anchorage-independent growth in vitro and tumorigenesis in xenograft animal models. We further documented that SET phosphorylation affects Akt activity. Collectively, our findings suggest that SET isoform 1 promotes oncogenesis in a mitotic phosphorylation-dependent manner.
UR - http://www.scopus.com/inward/record.url?scp=85065761963&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85065761963&partnerID=8YFLogxK
U2 - 10.1038/s41419-019-1621-2
DO - 10.1038/s41419-019-1621-2
M3 - Article
C2 - 31097686
AN - SCOPUS:85065761963
SN - 2041-4889
VL - 10
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 6
M1 - 385
ER -