Skip to main content
eScholarship
Open Access Publications from the University of California

RAP2 mediates mechanoresponses of the Hippo pathway

  • Author(s): Meng, Z
  • Qiu, Y
  • Lin, KC
  • Kumar, A
  • Placone, JK
  • Fang, C
  • Wang, KC
  • Lu, S
  • Pan, M
  • Hong, AW
  • Moroishi, T
  • Luo, M
  • Plouffe, SW
  • Diao, Y
  • Ye, Z
  • Park, HW
  • Wang, X
  • Yu, FX
  • Chien, S
  • Wang, CY
  • Ren, B
  • Engler, AJ
  • Guan, KL
  • et al.

Published Web Location

https://doi.org/10.1038/s41586-018-0444-0
No data is associated with this publication.
Abstract

© 2018, Springer Nature Limited. Mammalian cells are surrounded by neighbouring cells and extracellular matrix (ECM), which provide cells with structural support and mechanical cues that influence diverse biological processes1. The Hippo pathway effectors YAP (also known as YAP1) and TAZ (also known as WWTR1) are regulated by mechanical cues and mediate cellular responses to ECM stiffness2,3. Here we identified the Ras-related GTPase RAP2 as a key intracellular signal transducer that relays ECM rigidity signals to control mechanosensitive cellular activities through YAP and TAZ. RAP2 is activated by low ECM stiffness, and deletion of RAP2 blocks the regulation of YAP and TAZ by stiffness signals and promotes aberrant cell growth. Mechanistically, matrix stiffness acts through phospholipase Cγ1 (PLCγ1) to influence levels of phosphatidylinositol 4,5-bisphosphate and phosphatidic acid, which activates RAP2 through PDZGEF1 and PDZGEF2 (also known as RAPGEF2 and RAPGEF6). At low stiffness, active RAP2 binds to and stimulates MAP4K4, MAP4K6, MAP4K7 and ARHGAP29, resulting in activation of LATS1 and LATS2 and inhibition of YAP and TAZ. RAP2, YAP and TAZ have pivotal roles in mechanoregulated transcription, as deletion of YAP and TAZ abolishes the ECM stiffness-responsive transcriptome. Our findings show that RAP2 is a molecular switch in mechanotransduction, thereby defining a mechanosignalling pathway from ECM stiffness to the nucleus.

Many UC-authored scholarly publications are freely available on this site because of the UC Academic Senate's Open Access Policy. Let us know how this access is important for you.

Main Content

This item is under embargo until September 11, 2019.