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Updated: Dec 29, 2025

All-optical Mechanobiology Interrogation of Yes-associated Protein in Human Cancer and Normal Cells using a Multi-functional System
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All-optical Mechanobiology Interrogation of Yes-associated Protein in Human Cancer and Normal Cells using a Multi-functional System

Published on: December 20, 2021

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Furry protein suppresses nuclear localization of yes-associated protein (YAP) by activating NDR kinase and binding to

Kazuki Irie1, Tomoaki Nagai1, Kensaku Mizuno2

  • 1Department of Molecular and Chemical Life Sciences, Graduate School of Life Sciences, Tohoku University, Aobayama, Sendai, Miyagi 980-8578, Japan.

The Journal of Biological Chemistry
|January 31, 2020
PubMed

Insights

Furry (FRY) protein retains yes-associated protein (YAP) in the cytoplasm by activating NDR1/2 kinases and directly binding to YAP. This dual mechanism is crucial for regulating YAP localization and preventing uncontrolled cell growth.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The Hippo signaling pathway is a critical regulator of cell proliferation and tumor suppression.
  • Yes-associated protein (YAP) is a key transcriptional coactivator whose nuclear localization promotes cell growth.
  • Large tumor suppressor kinases (LATS1/2) and Nuclear Dbf2-related kinases (NDR1/2) inactivate YAP by promoting its phosphorylation and cytoplasmic retention.

Purpose of the Study:

  • To investigate the role of the cytoplasmic protein Furry (FRY) in regulating the nuclear/cytoplasmic localization of YAP.
  • To elucidate the molecular mechanisms by which FRY influences YAP localization and Hippo pathway activity.

Main Methods:

  • Construction and analysis of FRY-knockout cell lines.
  • Assessment of YAP nuclear localization, NDR1/2 kinase activity, and YAP phosphorylation levels.
  • Co-precipitation assays to identify protein-protein interactions between FRY and YAP.

Main Results:

  • FRY depletion significantly increased YAP nuclear localization and decreased NDR1/2 kinase activity and YAP phosphorylation.
  • FRY suppresses YAP nuclear localization through NDR1/2 activation and an additional, independent mechanism involving direct binding to YAP.
  • The N-terminal region of FRY (amino acids 1-2400) is sufficient for binding to YAP and restoring cytoplasmic localization.

Conclusions:

  • FRY plays a vital role in maintaining YAP in the cytoplasm, thereby acting as a tumor suppressor.
  • FRY utilizes a dual mechanism involving NDR1/2 activation and direct YAP binding to sequester YAP in the cytoplasm.
  • FRY's function in YAP retention highlights its importance in regulating cell proliferation and preventing tumorigenesis.
Keywords:
Furry (FRY)Hippo pathwayNDR (nuclear Dbf2-related) kinasecancercell signalinggene knockoutlarge tumor suppressor kinase (LATS)phosphorylationprotein kinaseyes-associated protein (YAP)

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