Cyclin-dependent kinase 1 (CDK1)-mediated mitotic phosphorylation of the transcriptional co-repressor Vgll4 inhibits its tumor-suppressing activity

Yongji Zeng, Seth Stauffer, Jiuli Zhou, Xingcheng Chen, Yuanhong Chen, Jixin Dong

Research output: Contribution to journalArticle

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Abstract

The Hippo pathway is an evolutionarily conserved signaling pathway that plays important roles in stem cell biology, tissue homeostasis, and cancer development. Vestigial-like 4 (Vgll4) functions as a transcriptional co-repressor in the Hippo-Yes-associated protein (YAP) pathway. Vgll4 inhibits cell proliferation and tumor growth by competing with YAP for binding to TEA-domain proteins (TEADs). However, the mechanisms by which Vgll4 itself is regulated are unclear. Here we identified a mechanism that regulates Vgll4's tumor-suppressing function. We found that Vgll4 is phosphorylated in vitro and in vivo by cyclin-dependent kinase 1 (CDK1) during antimitotic drug-induced mitotic arrest and also in normal mitosis. We further identified Ser-58, Ser-155, Thr-159, and Ser-280 as the main mitotic phosphorylation sites in Vgll4. We also noted that the nonphosphorylatable mutant Vgll4-4A (S58A/S155A/T159A/S280A) suppressed tumorigenesis in pancreatic cancer cells in vitro and in vivo to a greater extent than did wild-type Vgll4, suggesting that mitotic phosphorylation inhibits Vgll4's tumor-suppressive activity. Consistent with these observations, the Vgll4-4A mutant possessed higher-binding affinity to TEAD1 than wild-type Vgll4. Interestingly, Vgll4 and Vgll4-4A markedly suppressed YAP and β-catenin signaling activity. Together, these findings reveal a previously unrecognized mechanism for Vgll4 regulation in mitosis and its role in tumorigenesis.

Original languageEnglish (US)
Pages (from-to)15028-15038
Number of pages11
JournalJournal of Biological Chemistry
Volume292
Issue number36
DOIs
StatePublished - Jan 1 2017

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CDC2 Protein Kinase
Co-Repressor Proteins
Phosphorylation
Tumors
Tissue homeostasis
Mitosis
Cytology
Antimitotic Agents
Catenins
Neoplasms
Carcinogenesis
Proteins
Cell proliferation
Stem cells
Pancreatic Neoplasms
Cells
Protein Binding
Cell Biology
Homeostasis
Stem Cells

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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Cyclin-dependent kinase 1 (CDK1)-mediated mitotic phosphorylation of the transcriptional co-repressor Vgll4 inhibits its tumor-suppressing activity. / Zeng, Yongji; Stauffer, Seth; Zhou, Jiuli; Chen, Xingcheng; Chen, Yuanhong; Dong, Jixin.

In: Journal of Biological Chemistry, Vol. 292, No. 36, 01.01.2017, p. 15028-15038.

Research output: Contribution to journalArticle

Zeng, Yongji ; Stauffer, Seth ; Zhou, Jiuli ; Chen, Xingcheng ; Chen, Yuanhong ; Dong, Jixin. / Cyclin-dependent kinase 1 (CDK1)-mediated mitotic phosphorylation of the transcriptional co-repressor Vgll4 inhibits its tumor-suppressing activity. In: Journal of Biological Chemistry. 2017 ; Vol. 292, No. 36. pp. 15028-15038.
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