Rho GEFs and GAPs: emerging integrators of extracellular matrix signaling

Small GTPases. 2015;6(1):16-9. doi: 10.4161/21541248.2014.989792.


Investigating cell migration in 3D settings has revealed that specific extracellular matrix environments require differential activities of the Rho GTPases for efficient migration. However, it is largely unknown how the activities of specific Rho GTPases are modulated to direct cell migration in response to different extracellular matrix cues. We have recently reported that extracellular matrix-dependent regulation of a specific Rho GEF is a fundamental mechanism governing cell migration in different microenvironments, providing a direct mechanism for extracellular matrix-specific regulation of Rho GTPase activity directing cell motility. We discovered that the Rho GEF βPix has a unique function during cell migration in fibrillar collagen environments by restraining RhoA signaling through a conserved signaling axis involving Cdc42 and the Rho GAP srGAP1. In this Commentary, we expand upon this new pathway and discuss potential mechanotransductive and therapeutic applications. Additionally, we speculate on a generalized role for Rho GEFs and GAPs in providing localized, context-dependent responses to the cellular microenvironment during cell migration and other cellular processes.

Keywords: 3D migration; ECM, extracellular matrix; FRET, Fluorescence resonance energy transfer; GAP, GTPase activating protein; GEF, Guanine nucleotide exchange factor; HUVEC, Human umbilical cord vein endothelial cell; T526, Threonine 526; extracellular matrix; rho GAP; rho GEF; rho GTPase.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Cell Movement
  • Collagen / metabolism
  • Extracellular Matrix / genetics
  • Extracellular Matrix / metabolism*
  • Fibronectins / metabolism
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism
  • Humans
  • Rho Guanine Nucleotide Exchange Factors / genetics
  • Rho Guanine Nucleotide Exchange Factors / metabolism*
  • Signal Transduction*
  • rho GTP-Binding Proteins / genetics
  • rho GTP-Binding Proteins / metabolism


  • Fibronectins
  • GTPase-Activating Proteins
  • Rho Guanine Nucleotide Exchange Factors
  • rho GTPase-activating protein
  • Collagen
  • rho GTP-Binding Proteins