Back to Search Start Over

The Primate-specific Protein TBC1D3 Is Required for Optimal Macropinocytosis in a Novel ARF6-dependent Pathway

Authors :
Andrea Palamidessi
Massimiliano Garrè
Flavia Troglio
Albino Troilo
Pier Paolo Di Fiore
Alessandro Pizzigoni
Giorgio Scita
Emanuela Frittoli
Stefano Confalonieri
Letizia Lanzetti
Mitsunori Fukuda
Source :
Molecular Biology of the Cell. 19:1304-1316
Publication Year :
2008
Publisher :
American Society for Cell Biology (ASCB), 2008.

Abstract

The generation of novel genes and proteins throughout evolution has been proposed to occur as a result of whole genome and gene duplications, exon shuffling, and retrotransposition events. The analysis of such genes might thus shed light into the functional complexity associated with highly evolved species. One such case is represented by TBC1D3, a primate-specific gene, harboring a TBC domain. Because TBC domains encode Rab-specific GAP activities, TBC-containing proteins are predicted to play a major role in endocytosis and intracellular traffic. Here, we show that the TBC1D3 gene originated late in evolution, likely through a duplication of the RNTRE locus, and underwent gene amplification during primate speciation. Despite possessing a TBC domain, TBC1D3 is apparently devoid of Rab-GAP activity. However, TBC1D3 regulates the optimal rate of epidermal growth factor–mediated macropinocytosis by participating in a novel pathway involving ARF6 and RAB5. In addition, TBC1D3 binds and colocalize to GGA3, an ARF6-effector, in an ARF6-dependent manner, and synergize with it in promoting macropinocytosis, suggesting that the two proteins act together in this process. Accordingly, GGA3 siRNA-mediated ablation impaired TBC1D3-induced macropinocytosis. We thus uncover a novel signaling pathway that appeared after primate speciation. Within this pathway, a TBC1D3:GGA3 complex contributes to optimal propagation of signals, ultimately facilitating the macropinocytic process.

Details

ISSN :
19394586 and 10591524
Volume :
19
Database :
OpenAIRE
Journal :
Molecular Biology of the Cell
Accession number :
edsair.doi.dedup.....bf2500423045976bf958d057f166e57b