title: p66ShcCouples Mechanical Signals to RhoA through Focal Adhesion Kinase-Dependent Recruitment of p115-RhoGEF and GEF-H1.
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/p66Shccomplex 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/p52Shccomplex 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 p66Shcand its associated Rho GEFs. These studies reveal the binary and exclusive assignment of p66Shcand p52Shcto 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.
authors: Department of Internal Medicine, Division of Pulmonary and Critical Care, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors: Ru-Feng
authors: RF
authors: Wu
authors: Department of Internal Medicine, Division of Pulmonary and Critical Care, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors: Chengxu
authors: C
authors: Liao
authors: Department of Internal Medicine, Division of Pulmonary and Critical Care, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors: Guosheng
authors: G
authors: Fu
authors: Department of Bioengineering, University of Texas at Dallas, Richardson, Texas, USA.
authors: Heather N
authors: HN
authors: Hayenga
authors: Department of Chemistry, University of Texas at Dallas, Richardson, Texas, USA.
authors: Kejia
authors: K
authors: Yang
authors: Department of Immunology, Biochemistry and Molecular Biology, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin, China.
authors: Zhenyi
authors: Z
authors: Ma
authors: Department of Immunology, Biochemistry and Molecular Biology, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin, China.
authors: Zhe
authors: Z
authors: Liu
authors: Department of Internal Medicine, Division of Pulmonary and Critical Care, University of Texas Southwestern Medical Center, Dallas, Texas, USA Lance.terada@utsouthwestern.edu.
authors: Lance S
authors: LS
authors: Terada