Solo/Trio8, a Membrane-Associated Short Isoform of Trio, Modulates Endosome Dynamics and Neurite Elongation

Abstract

With DNA microarrays, we identified a gene, termed Solo, that is downregulated in the cerebellum of Purkinje cell degeneration mutant mice. Solo is a mouse homologue of rat Trio8-one of multiple Trio isoforms recently identified in rat brain. Solo/Trio8 contains N-terminal sec14-like and spectrin-like repeat domains followed by a single guanine nucleotide exchange factor 1 (GEF1) domain, but it lacks the C-terminal GEF2, immunoglobulin-like, and kinase domains that are typical of Trio. Solo/Trio8 is predominantly expressed in Purkinje neurons of the mouse brain, and expression begins following birth and increases during Purkinje neuron maturation. We identified a novel C-terminal membrane-anchoring domain in Solo/Trio8 that is required for enhanced green fluorescent protein-Solo/Trio8 localization to early endosomes (positive for both early-endosome antigen 1 [EEA1] and Rab5) in COS-7 cells and primary cultured neurons. Solo/Trio8 overexpression in COS-7 cells augmented the EEA1-positive early-endosome pool, and this effect was abolished via mutation and inactivation of the GEF domain or deletion of the C-terminal membrane-anchoring domain. Moreover, primary cultured neurons transfected with Solo/Trio8 showed increased neurite elongation that was dependent on these domains. These results suggest that Solo/Trio8 acts as an early-endosome-specific upstream activator of Rho family GTPases for neurite elongation of developing Purkinje neurons.

Recruitment of Actin Modifiers to TrkA Endosomes Governs Retrograde NGF Signaling and Survival

“…Under certain conditions, Rac1 is necessary for cofilin activation through the promotion of dephosphorylation of cofilin Ser 3 (Pandey et al, 2009) and it is implicated in Trk receptor endocytosis and transport (Philippidou et al, 2011; Valdez et al, 2007). Additionally, regulators of Rac1 activity are implicated in the control of endosomal trafficking (Sun et al, 2006). Therefore, we next asked whether Rac1 mediates NGF/TrkA signaling endosome formation, maturation and/or trafficking in sympathetic neurons and if Rac1 signaling controls cofilin activity and/or its association with the TrkA endosome.…”

Plasma Membrane Association of p63 Rho Guanine Nucleotide Exchange Factor (p63RhoGEF) Is Mediated by Palmitoylation and Is Required for Basal Activity in Cells

“…The homologous C-terminal RhoGEF domains of Trio and Duet are also activated by G␣ q , presumably through a similar mechanism (13,14,41). However, because these proteins lack an obvious equivalent to the Cys string found in the N terminus of p63RhoGEF, they must have alternative mechanisms for membrane localization (42,43).…”

The many faces of the guanine-nucleotide exchange factor trio

“…Kalirin-7 (also known as Duo), -9 and -12 are expressed in the brain and differ in length at their C-terminus 13 . Several Trio isoforms, Trio A, B and D, are strongly expressed in the brain and during development, whereas Trio C, also known as Solo/Trio8, is exclusively expressed in the cerebellum 12 , 14 . All these splice variants include the N-terminal SEC14 and spectrin-repeats as well as the first DH-PH GEF domain.…”