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Vol. 19, Issue 4, 1304-1316, April 2008

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

Emanuela Frittoli^*,, Andrea Palamidessi^*,,, Alessandro Pizzigoni^*,,, Letizia Lanzetti, Massimiliano Garrè^*, Flavia Troglio^*, Albino Troilo^*, Mitsunori Fukuda^||,¶, Pier Paolo Di Fiore^*,,#, Giorgio Scita^*,,#, and Stefano Confalonieri^*

*IFOM, the FIRC Institute of Molecular Oncology Foundation, 20139 Milan, Italy; European Institute of Oncology, 20141 Milan, Italy; Department of Oncological Sciences, University of Turin, Institute for Cancer Research and Treatment, 10060 Candiolo, Torino, Italy; ^||Fukuda Initiative Research Unit, RIKEN (The Institute of Physical and Chemical Research), Saitama 351-0198, Japan; ^¶Laboratory of Membrane Trafficking Mechanisms, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai, Miyagi 980-8578, Japan; and ^#University of Milan, 20122 Milan, Italy

Submitted June 21, 2007; Revised January 2, 2008; Accepted January 9, 2008
Monitoring Editor: Sandra Schmid

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.

These authors contributed equally to this work.

Address correspondence to: Stefano Confalonieri (stefano.confalonieri{at}ifom-ieo-campus.it) or Giorgio Scita (giorgio.scita{at}ifom-ieo-campus.it)

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