RhoGDIγ: A GDP-dissociation inhibitor for Rho proteins with preferential expression in brain and pancreas

Abstract

GDP-dissociation inhibitors (GDIs) play a primary role in modulating the activation of GTPases and may also be critical for the cellular compartmentalization of GTPases. RhoGDI and GDI͞D4 are two currently known GDIs for the Rho-subfamily of GTPases. Using their cDNAs to screen a human brain cDNA library under low stringency, we have cloned a homologous cDNA preferentially expressed at high levels in brain and pancreas. The predicted protein, named RhoGDI␥, is Ϸ50% identical to GDI͞D4 and RhoGDI. It binds to CDC42 and RhoA with less affinity compared with RhoGDI and does not bind with Rac1, Rac2, or Ras. RhoGDI␥ functions as a GDI for CDC42 but with Ϸ20 times less efficiency than RhoGDI. Immunohistochemical studies showed a diffuse punctate distribution of the protein in the cytoplasm with concentration around the nucleus in cytoplasmic vesicles. Overexpression of the protein in baby hamster kidney cells caused the cells to round up with loss of stress fibers. A distinct hydrophobic amino terminus in RhoGDI␥, not seen in the other two RhoGDIs, could provide a mechanism for localization of the GDI to specific membranous compartment thus determining function distinct from RhoGDI or GDI͞D4. Our results provide evidence that there is a family of GDIs for the Rho-related GTPases and that they differ in binding affinity, target specificity, and tissue expression. We propose that RhoGDI be renamed RhoGDI␣ and GDID4 be renamed RhoGDI␤. The new GDI should widen the scope of investigation of this important class of regulatory protein.

Rho-family GTPases: it's not only Rac and Rho (and I like it)

“…The three conventional GDIs seem to have different Rho-binding specificites. Whereas RhoGDI-1 binds well to RhoA, Rac1 and Cdc42, RhoGDI-3 binds well to RhoB and RhoG, and seemingly with a lower affinity to RhoA and Cdc42, but not to Rac1 and Rac2 (Adra et al, 1997;Zalcman et al, 1996). The targets for RhoGDI-2 remain unclear, but it does not bind well to RhoA, Rac1 or Cdc42 (Olofsson, 1999).…”

Rho family proteins and Ras transformation: the RHOad less traveled gets congested

“…A cytosolic complex with RhoGDI is disrupted during Rho membrane translocation and activation by GEFs. Two additional RhoGDIs include the hematopoietic cell speci®c D4-GDI/LY-GDI (Lelias et al, 1993;Scherle and Staudt, 1993) and RhoGDIg/RhoGDI-3, which is preferentially expressed in brain, pancreas and other tissues (Adra et al, 1997;Zalcman et al, 1996).…”

Interaction of radixin with Rho small G protein GDP/GTP exchange protein Dbl

“…The conversion from the GDP-bound form to the GTP-bound form is regulated by two types of regulators: GDP/GTP exchange protein (GEP), which stimulates this reaction and GDP dissociation inhibitor (GDI), which inhibits this reaction. There are three isoforms of GDI: Rho GDI, Ly/D4-GDI and Rho GDI-3 (Fukumoto et al, 1990;Ueda et al, 1990;Lelias et al, 1993;Scherle et al, 1993;Zalcman et al, 1996;Adra et al, 1997). Of these GDIs, Rho GDI was originally isolated and well characterized in our laboratory.…”