TBC1D3, a hominoid oncoprotein, is encoded by a cluster of paralogues located on chromosome 17q12

Hodzic, Didier; Chen, Kong; Wainszelbaum, Marisa J.; Charron, Audra J.; Su, Xiong; Stahl, Philip D.

doi:10.1016/j.ygeno.2006.05.009

Cited by 52 publications

(49 citation statements)

References 12 publications

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“…The amplified locus at band 17q12 encompasses 2 of 8 paralogs of the hominoid oncoprotein TBC1D3. 26 Because of limiting patient material, validation of the gain at band 17q12 by FISH analysis was performed on MDS-L cells using 2 BAC clones: one BAC clone (RP11-72I20) within the region of interest and one BAC clone (RP11-686E5) outside the region of interest. As shown in Figure 2C, FISH analysis confirmed an increase in copy number (ϳ 20% of cells had Ͼ 3 copies per cell) at band 17q12, which was not detectable on 3 BM samples from healthy donors.…”

Section: Amplification Of the Hominoid Oncoprotein Tbc1d3 Is A Novel mentioning

confidence: 99%

High-resolution whole genome tiling path array CGH analysis of CD34+ cells from patients with low-risk myelodysplastic syndromes reveals cryptic copy number alterations and predicts overall and leukemia-free survival

Starczynowski

Vercauteren

Telenius

et al. 2008

Blood

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Section: Amplification Of the Hominoid Oncoprotein Tbc1d3 Is A Novel mentioning

confidence: 99%

High-resolution whole genome tiling path array CGH analysis of CD34+ cells from patients with low-risk myelodysplastic syndromes reveals cryptic copy number alterations and predicts overall and leukemia-free survival

Starczynowski

Vercauteren

Telenius

et al. 2008

Blood

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“…Seven of these TBC1D3-related regions (showing ϳ99% of identity over Ͼ10 kb) contain ORFs potentially coding for full-length proteins (data not shown) and display a complex pattern of expression in several tissues (Hodzic et al, 2006). In addition specific patterns of expression of these paralogs were observed in different normal human tissues and altered in several prostate tumors in comparison to healthy prostate tissue (Hodzic et al, 2006). Conversely, the remaining two paralogs display in-frame stop codons and frameshifts caused by insertion/deletion of single nucleotides in the genomic sequence.…”

Section: Tbc1d3 the Paralog Of Human Rntre Underwent Gene Duplicatimentioning

confidence: 99%

“…The similarity among these genomic regions is not limited to the exons, but also extends to the introns, indicating that entire TBC1D3 locus underwent duplication. Seven of these TBC1D3-related regions (showing ϳ99% of identity over Ͼ10 kb) contain ORFs potentially coding for full-length proteins (data not shown) and display a complex pattern of expression in several tissues (Hodzic et al, 2006). In addition specific patterns of expression of these paralogs were observed in different normal human tissues and altered in several prostate tumors in comparison to healthy prostate tissue (Hodzic et al, 2006).…”

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confidence: 98%

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

Frittoli

Palamidessi

Pizzigoni

et al. 2008

MBoC

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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 primatespecific 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. INTRODUCTIONGene duplication, exon shuffling, and retrotransposition events played crucial roles during vertebrate evolution (Long, 2001;McLysaght et al., 2002;Brosius, 2003). About 5% of the human genome is composed of duplicated segments that emerged during the past 35 million years of primate evolution, resulting in the generation of novel protein functions (Courseaux and Nahon, 2001;Taylor and Raes, 2004).One of the cellular processes, whose regulation has became more and more complex and tightly regulated during evolution is endocytosis. Endocytosis serves to maintain cellular and organismal homeostasis by mediating the uptake of fluids, solutes, and signaling molecules and their receptors. Multiple mechanisms of endocytosis operate within a single cell (Conner and Schmid, 2003). Among them, two major categories are phagocytosis and pinocytosis, which mediate the uptake of particles or of fluid, respectively (Conner and Schmid, 2003).Pinocytosis encompasses a variety of different membraneentry routes and is invariably characterized by the relatively small size (50 -150 nm) of the internalized particles. Large volumes of fluid are, instead, engulfed by extension, folding, and closure of plasma membranes (PM) through a process termed macropinocytosis (Swanson and Watts, 1995). Macropinocytosis displays many similarities to phagocytosis; the biochemical and cellular components of these endocytic mechanisms have been best characterized in hematopoietic cells, in processes such as phagocytosis by macrophages in response to Fc receptor stimulation, or ma...

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“…Still, we know little about this small group of genes, which presumably modulate or regulate signaling pathways that have evolved to a higher level of complexity and that distinguish hominoids and humans from less complex species. TBC1D3 belongs to a hominoid-specific gene family with no known orthologs outside of the primate lineage (1). TBC1D3 was originally identified by Pei et al as a prostate and breast cancer oncogene (2).…”

mentioning

confidence: 99%

The Hominoid-specific Oncogene TBC1D3 Activates Ras and Modulates Epidermal Growth Factor Receptor Signaling and Trafficking

Wainszelbaum

Charron

Chen

et al. 2008

Journal of Biological Chemistry

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Hominoid-and human-specific genes may have evolved to modulate signaling pathways of a higher order of complexity. TBC1D3 is a hominoid-specific oncogene encoded by a cluster of eight paralogs on chromosome 17. Initial work indicates that TBC1D3 is widely expressed in human tissues (Hodzic, D., Kong, C., Wainszelbaum, M. J., Charron, A. J., Su, X., and Stahl, P. D. (2006) Genomics 88, 731-736). In this study, we show that TBC1D3 expression has a powerful effect on cell proliferation that is further enhanced by epidermal growth factor (EGF) in both human and mouse cell lines. EGF activation of the Erk and protein kinase B/Akt pathways is enhanced, both in amplitude and duration, by TBC1D3 expression, whereas RNA interference silencing of TBC1D3 suppresses the activation. Light microscopy and Western blot experiments demonstrate that increased signaling in response to EGF is coupled with a significant delay in EGF receptor (EGFR) trafficking and degradation, which significantly extends the life span of EGFR. Moreover, TBC1D3 suppresses polyubiquitination of the EGFR and the recruitment of c-Cbl. Using the Ras binding domain of Raf1 to monitor GTP-Ras we show that TBC1D3 expression enhances Ras activation in quiescent cells, which is further increased by EGF treatment. We speculate that TBC1D3 may alter Ras GTP loading. We conclude that the expression of TBC1D3 generates a delay in EGFR degradation, a decrease in ubiquitination, and a failure to recruit adapter proteins that ultimately dysregulate EGFR signal transduction and enhance cell proliferation. Altered growth factor receptor trafficking and GTP-Ras turnover may be sites where recently evolved genes such as TBC1D3 selectively modulate signaling in hominoids and humans.

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TBC1D3, a hominoid oncoprotein, is encoded by a cluster of paralogues located on chromosome 17q12

Cited by 52 publications

References 12 publications

High-resolution whole genome tiling path array CGH analysis of CD34+ cells from patients with low-risk myelodysplastic syndromes reveals cryptic copy number alterations and predicts overall and leukemia-free survival

High-resolution whole genome tiling path array CGH analysis of CD34+ cells from patients with low-risk myelodysplastic syndromes reveals cryptic copy number alterations and predicts overall and leukemia-free survival

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

The Hominoid-specific Oncogene TBC1D3 Activates Ras and Modulates Epidermal Growth Factor Receptor Signaling and Trafficking

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