Dimerization and cytoplasmic localization regulate hippo kinase signaling activity in organ size control

Yunyun Jin, Liang Dong, Yi Lu, Wenqing Wu, Qian Hao, Zhaocai Zhou, Jin Jiang, Yun Zhao, Lei Zhang

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

The Hippo (Hpo) signaling pathway controls organ size by regulating the balance between cell proliferation and apoptosis. Although the Hpo function is conserved, little is known about the mechanism of how its kinase activity is regulated. Based on structural information, we performed mutation-function analysis and provided in vitro and in vivo evidence that Hpo activation requires proper dimerization of its N-terminal kinase domain as well as the C-terminal SARAH domain. Hpo carrying point mutation M242E can still dimerize, yet the dimers formed between intermolecular kinase domains were altered in conformation. As a result, autophosphorylation of Hpo at Thr-195 was blocked, and its kinase activity was abolished. In contrast, Hpo carrying I634D, a single mutation introduced in the Hpo C-terminal SARAH domain, disrupted the dimerization of the SARAHdomain, leading to reduced Hippo activity.We also find that theHpoC-terminal half contains two nuclear export signals that promote cytoplasmic localization and activity of Hpo. Taken together, our results suggest that dimerization and nucleocytoplasmic translocation of Hpo are crucial for its biological function and indicate that a proper dimer conformation of the kinase domain is essential for Hpo autophosphorylation and kinase activity.

Original languageEnglish (US)
Pages (from-to)5784-5796
Number of pages13
JournalJournal of Biological Chemistry
Volume287
Issue number8
DOIs
StatePublished - Feb 17 2012

Fingerprint

Organ Size
Dimerization
Phosphotransferases
Dimers
Conformations
Nuclear Export Signals
Mutation
Cell proliferation
Point Mutation
Chemical activation
Cell Proliferation
Apoptosis

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Dimerization and cytoplasmic localization regulate hippo kinase signaling activity in organ size control. / Jin, Yunyun; Dong, Liang; Lu, Yi; Wu, Wenqing; Hao, Qian; Zhou, Zhaocai; Jiang, Jin; Zhao, Yun; Zhang, Lei.

In: Journal of Biological Chemistry, Vol. 287, No. 8, 17.02.2012, p. 5784-5796.

Research output: Contribution to journalArticle

Jin, Yunyun ; Dong, Liang ; Lu, Yi ; Wu, Wenqing ; Hao, Qian ; Zhou, Zhaocai ; Jiang, Jin ; Zhao, Yun ; Zhang, Lei. / Dimerization and cytoplasmic localization regulate hippo kinase signaling activity in organ size control. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 8. pp. 5784-5796.
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