p66Shc couples mechanical signals to RhoA through focal adhesion kinase-dependent recruitment of p115-RhoGEF and GEF-H1

Ru Feng Wu, Chengxu Liao, Guosheng Fu, Heather N. Hayeng, Kejia Yang, Zhenyi Ma, Zhe Liu, Lance S. Terada

Research output: Contribution to journalArticle

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Abstract

Tissue cells respond to changes in tensional forces with proliferation or death through the control of RhoA. However, the response coupling mechanisms that link force with RhoA activation are poorly understood. We found that tension applied to fibronectin- coated microbeads caused recruitment of all three isoforms of the Shc adapter (p66Shc, p52Shc, and p46Shc) to adhesion complexes. The Shc PTB domain was necessary and sufficient for this recruitment, and screening studies revealed the direct interactions with the FERM domain of focal adhesion kinase (FAK) that were required for Shc translocation to adhesion complexes. The FAK/p66Shc complex specifically bound and activated the Rho guanyl exchange factors (GEFs) p115-RhoGEF and GEF-H1, leading to tension-induced RhoA activation. In contrast, the FAK/p52Shc complex bound SOS1 but not the Rho GEFs to mediate tension-induced Ras activation. Nuclear translocation and activation of the YAP/TAZ transcription factors on firm substrates required the FAK/p66Shc/Rho GEF complex, and both proliferation on firm substrates and anoikis in suspension required signaling through p66Shc and its associated Rho GEFs. These studies reveal the binary and exclusive assignment of p66Shc and p52Shc to tension-induced Rho or Ras signals, respectively, and suggest an integrated role for the two Shc isoforms in coordinating the cellular response to mechanical stimuli.

Original languageEnglish (US)
Pages (from-to)2824-2837
Number of pages14
JournalMolecular and Cellular Biology
Volume36
Issue number22
DOIs
StatePublished - Jan 1 2016

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Rho Guanine Nucleotide Exchange Factors
Focal Adhesion Protein-Tyrosine Kinases
Protein Isoforms
Anoikis
Microspheres
Fibronectins
Suspensions
Transcription Factors

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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p66Shc couples mechanical signals to RhoA through focal adhesion kinase-dependent recruitment of p115-RhoGEF and GEF-H1. / Wu, Ru Feng; Liao, Chengxu; Fu, Guosheng; Hayeng, Heather N.; Yang, Kejia; Ma, Zhenyi; Liu, Zhe; Terada, Lance S.

In: Molecular and Cellular Biology, Vol. 36, No. 22, 01.01.2016, p. 2824-2837.

Research output: Contribution to journalArticle

Wu, Ru Feng ; Liao, Chengxu ; Fu, Guosheng ; Hayeng, Heather N. ; Yang, Kejia ; Ma, Zhenyi ; Liu, Zhe ; Terada, Lance S. / p66Shc couples mechanical signals to RhoA through focal adhesion kinase-dependent recruitment of p115-RhoGEF and GEF-H1. In: Molecular and Cellular Biology. 2016 ; Vol. 36, No. 22. pp. 2824-2837.
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