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Different regulation of the Trio Dbl-Homology domains by their associated PH domains

J-M Bellanger1, S Estrach, S Schmidt

  • 1CRBM-CNRS, FRE 2593 1919, route de Mende, 34293 Montpellier Cédex 5, France.

Biology of the Cell
|January 15, 2004
PubMed

Insights

The two Pleckstrin Homology (PH) domains of Trio, a Guanine nucleotide exchange factor (GEF), have distinct roles in regulating Rho-GTPase activity. TrioPH1 targets proteins to the cytoskeleton and activates JNK, while TrioPH2 inhibits RhoA activity.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Signal Transduction

Background:

  • Rho-GTPases are key regulators of the actin cytoskeleton, cell migration, and gene expression.
  • Guanine nucleotide exchange factors (GEFs) activate Rho-GTPases by promoting GTP binding.
  • Trio is a unique GEF with two catalytic Dbl-Homology (DH) domains, GEFD1 and GEFD2, and associated Pleckstrin Homology (PH) domains.

Purpose of the Study:

  • To elucidate the specific functions of the two PH domains of Trio in regulating its GEF activity and downstream signaling.
  • To investigate the roles of TrioPH1 and TrioPH2 in cytoskeletal organization, JNK activation, and neurite outgrowth.

Main Methods:

  • Site-directed mutagenesis to delete PH domains.
  • Expression of Trio constructs in cell lines (e.g., PC12).
  • Assessment of actin cytoskeleton remodeling, JNK pathway activation, and GEF activity assays.

Main Results:

  • TrioPH1 is essential for GEFD1-mediated actin remodeling and JNK activation, acting as a cytoskeletal targeting signal.
  • TrioPH1 also activates the JNK pathway independently of GEFD2's catalytic activity.
  • TrioPH2 inhibits GEFD2-mediated stress fiber formation and RhoA GEF activity.
  • Only TrioPH1 is required for Trio-induced neurite outgrowth in PC12 cells.

Conclusions:

  • The two PH domains of Trio possess distinct and non-redundant functions in controlling Trio's GEF activity and cellular responses.
  • TrioPH1 acts as a regulatory and targeting module, crucial for Trio's role in cytoskeletal dynamics and neuronal differentiation.
  • TrioPH2 functions as an inhibitor of Trio's RhoA-specific GEF activity.

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