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The Primate-specific Protein TBC1D3 Is Required for Optimal Macropinocytosis in a Novel ARF6-dependent Pathway
- 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.
- Subjects :
- Primates
Oncogene Proteins
GTPase-activating protein
macropinocytosis
Molecular Sequence Data
Retrotransposon
Computational biology
Biology
Exon shuffling
Genome
Evolution, Molecular
Gene Duplication
Proto-Oncogene Proteins
Chlorocebus aethiops
Gene duplication
endocytosis
Animals
Humans
Gene silencing
Amino Acid Sequence
Gene Silencing
Molecular Biology
Gene
Phylogeny
rab5 GTP-Binding Proteins
Genetics
Sequence Homology, Amino Acid
ADP-Ribosylation Factors
GTPase-Activating Proteins
Arf
Articles
Cell Biology
Recombinant Proteins
Protein Structure, Tertiary
Adaptor Proteins, Vesicular Transport
ADP-Ribosylation Factor 6
COS Cells
Pinocytosis
HeLa Cells
Subjects
Details
- ISSN :
- 19394586 and 10591524
- Volume :
- 19
- Database :
- OpenAIRE
- Journal :
- Molecular Biology of the Cell
- Accession number :
- edsair.doi.dedup.....bf2500423045976bf958d057f166e57b